Azaindoles useful as inhibitors of janus kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

CROSS REFERENCE TO RELATED APPLICATION

This divisional application claims the benefit of U.S. application Ser.No. 14/339,514, filed on Jul. 24, 2014, which is a divisional of U.S.application Ser. No. 13/870,173, filed on Apr. 25, 2013, which is adivisional of U.S. application Ser. No. 13/409,702, filed on Mar. 1,2012, which is a division of U.S. application Ser. No. 12/775,885, filedon May 7, 2010, which is a continuation of U.S. application Ser. No.11/654,375, filed Jan. 17, 2007, which claims the benefit of U.S.Provisional Application No. 60/759,367, filed Jan. 17, 2006 and U.S.Provisional Application No. 60/842,471, filed Sep. 6, 2006. Each ofthese applications is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of Januskinases (JAK). The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The Janus kinases (JAK) are a family of tyrosine kinases consisting ofJAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokinesignaling. The down-stream substrates of the JAK family of kinasesinclude the signal transducer and activator of transcription (STAT)proteins. JAK/STAT signaling has been implicated in the mediation ofmany abnormal immune responses such as allergies, asthma, autoimmunediseases such as transplant rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis as well as in solid andhematologic malignancies such as leukemias and lymphomas. JAK2 has alsobeen implicated in myeloproliferative disorders, which includepolycythemia vera, essential thrombocythemia, chronic idiopathicmyelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloidleukemia, chronic myelomonocytic leukemia, chronic eosinophilicleukemia, hypereosinophilic syndrome and systematic mast cell disease.

Accordingly, there is a great need to develop compounds useful asinhibitors of protein kinases. In particular, it would be desirable todevelop compounds that are useful as inhibitors of JAK family kinases.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of protein kinases, particularly the JAK family kinases.These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein X¹, R¹, R² and R³are as defined herein.

These compounds, and pharmaceutically acceptable compositions thereof,are useful for treating or lessening the severity of a variety ofdisorders, including proliferative disorders, cardiac disorders,neurodegenerative disorders, autoimmune disorders, conditions associatedwith organ transplantation, inflammatory disorders, or immunologicallymediated disorders in a patient.

The compounds and compositions provided by this invention are alsouseful for the study of JAK kinases in biological and pathologicalphenomena; the study of intracellular signal transduction pathwaysmediated by such kinases; and the comparative evaluation of new kinaseinhibitors.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75^(th) Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of one or more hydrogen radicals in a given structure withthe radical of a specified substituent. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group. When more than one position in agiven structure can be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at each position.

As described herein, when the term “optionally substituted” precedes alist, said term refers to all of the subsequent substitutable groups inthat list. If a substituent radical or structure is not identified ordefined as “optionally substituted”, the substituent radical orstructure is unsubstituted. For example, if X is halogen; optionallysubstituted C₁₋₃alkyl or phenyl; X may be either optionally substitutedalkyl or optionally substituted phenyl. Likewise, if the term“optionally substituted” follows a list, said term also refers to all ofthe substitutable groups in the prior list unless otherwise indicated.For example: if X is halogen, C₁₋₃alkyl or phenyl wherein X isoptionally substituted by J^(X), then both C₁₋₃alkyl and phenyl may beoptionally substituted by J^(X). As is apparent to one having ordinaryskill in the art, groups such as H, halogen, NO₂, CN, NH₂, OH, or OCF₃would not be included because they are not substitutable groups.

Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, preferably, their recovery,purification, and use for one or more of the purposes disclosed herein.In some embodiments, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and In yet other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups. Further examples of aliphatic groups includemethyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.

The term “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to ahydrocarbon that is completely saturated or that contains one or moreunits of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule, and wherein anyindividual ring in said bicyclic ring system has 3-7 members. Unlessotherwise specified, the term “cycloaliphatic” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon. Suitablecycloaliphatic groups include, but are not limited to, cycloalkyl,cycloalkenyl, and cycloalkynyl. Further examples of aliphatic groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cycloheptenyl.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used hereinrefers to a monocyclic, bicyclic, or tricyclic ring system in which oneor more ring members are an independently selected heteroatom and thatis completely saturated or that contains one or more units ofunsaturation, but which is not aromatic, that has a single point ofattachment to the rest of the molecule. In some embodiments, the“heterocycle”, “heterocyclyl” or “heterocyclic” group has three tofourteen ring members in which one or more ring members is a heteroatomindependently selected from oxygen, sulfur, nitrogen, or phosphorus, andeach ring in the system contains 3 to 7 ring members.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,phosphorus, or silicon, the quaternized form of any basic nitrogen, or asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic carbocyclic ring systems having a total of sixto fourteen ring members, wherein at least one ring in the system isaromatic, wherein each ring in the system contains 3 to 7 ring membersand that has a single point of attachment to the rest of the molecule.The term “aryl” may be used interchangeably with the term “aryl ring”.Examples of aryl rings would include phenyl, naphthyl, and anthracene.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, wherein eachring in the system contains 3 to 7 ring members and that has a singlepoint of attachment to the rest of the molecule. The term “heteroaryl”may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

Further examples of heteroaryl rings include the following monocycles:2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl,5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g.,2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including heteroaralkyl andheteroarylalkoxy and the like) group may contain one or moresubstituents. Suitable substituents on the unsaturated carbon atom of anaryl or heteroaryl group are selected from those listed in thedefinitions of R² and R⁴ below. Other suitable substituents include:halogen; —R^(∘); —OR^(∘); —SR^(∘); 1,2-methylenedioxy;1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R^(∘); —O(Ph)optionally substituted with R^(∘); —(CH₂)₁₋₂(Ph), optionally substitutedwith R^(∘); —CH═CH(Ph), optionally substituted with R^(∘); —NO₂; —CN;—N(R^(∘))₂; —NR^(∘)C(O)R^(∘); —NR^(∘)C(S)R^(∘); —NR^(∘)C(O)N(R^(∘))₂;—NR^(∘)C(S)N(R^(∘))₂; —NR^(∘)CO₂R^(∘); —NR^(∘)NR^(∘)C(O)R^(∘);—NR^(∘)NR^(∘)C(O)N(R^(∘))₂; —NR^(∘)NR^(∘)CO₂R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —CO₂R^(∘); —C(O)R^(∘); —C(S)R^(∘);—C(O)N(R^(∘))₂; —C(S)N(R^(∘))₂; —OC(O)N(R^(∘))₂; —OC(O)R^(∘);—C(O)N(OR^(∘))R^(∘); —C(NOR^(∘))R^(∘); —S(O)₂R^(∘); —S(O)₃R^(∘);—SO₂N(R^(∘))₂; —S(O)R^(∘); —NR^(∘)SO₂N(R^(∘))₂; —NR^(∘)SO₂R^(∘);—N(OR^(∘))R^(∘); —C(═NH)—N(R^(∘))₂; or —(CH₂)₀₋₂NHC(O)R^(∘); whereineach independent occurrence of R^(∘)is selected from hydrogen,optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph), or, twoindependent occurrences of R^(∘), on the same substituent or differentsubstituents, taken together with the atom(s) to which each R^(∘)groupis bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring ora 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclylring has 1-3 heteroatoms independently selected from nitrogen, oxygen,or sulfur. Optional substituents on the aliphatic group of R^(∘)areselected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen,C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic),O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of theforegoing C₁₋₄aliphatic groups of R^(∘)is unsubstituted.

In some embodiments, an aliphatic or heteroaliphatic group, or anon-aromatic heterocyclic ring may contain one or more substituents.Suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic heterocyclic ring areselected from those listed above for the unsaturated carbon of an arylor heteroaryl group and additionally include the following: ═O, ═S,═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,where each R* is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic. Optional substituents on the aliphatic groupof R* are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of anon-aromatic heterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, optionally substituted phenyl, optionallysubstituted —O(Ph), optionally substituted —CH₂(Ph), optionallysubstituted —(CH₂)₁₋₂(Ph); optionally substituted —CH═CH(Ph); or anunsubstituted 5-6 membered heteroaryl or heterocyclic ring having one tofour heteroatoms independently selected from oxygen, nitrogen, orsulfur, or, two independent occurrences of R⁺, on the same substituentor different substituents, taken together with the atom(s) to which eachR⁺group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroarylring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl orheterocyclyl ring has 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Optional substituents on the aliphaticgroup or the phenyl ring of R⁺are selected from NH₂, NH(C₁₋₄ aliphatic),N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂,CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R⁺isunsubstituted.

As detailed above, in some embodiments, two independent occurrences ofR^(∘)(or R⁺, or any other variable similarly defined herein), may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring. Exemplary rings that are formed when two independentoccurrences of R^(∘)(or R⁺, or any other variable similarly definedherein) are taken together with the atom(s) to which each variable isbound include, but are not limited to the following: a) two independentoccurrences of R^(∘)(or R⁺, or any other variable similarly definedherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R^(∘))₂, where both occurrences ofR^(∘)are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(∘)(or R⁺, or any other variable similarly definedherein) that are bound to different atoms and are taken together withboth of those atoms to form a ring, for example where a phenyl group issubstituted with two occurrences of

these two occurrences of R^(∘)are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(∘)(or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with said otheratom or group. Examples of such atoms or groups would include, but arenot limited to, —NR—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)CO—, —C(O)—,—C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, —NRSO₂NR—, —SO—, or —SO₂—, wherein R is defined herein.Unless otherwise specified, the optional replacements form a chemicallystable compound. Optional interruptions can occur both within the chainand at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound. Unless otherwise specified, if thereplacement or interruption occurs at the terminal end, the replacementatom is bound to an H on the terminal end. For example, if —CH₂CH₂CH₃were optionally interrupted with —O—, the resulting compound could be—OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below), representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, Compound arepresents possible substitution in any of the positions shown inCompound b.

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inCompound c, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Compound d, Y is an optionallysubstituent for ring A only, and X is an optional substituent for ring Bonly.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structuresexcept for the replacement of hydrogen by deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention. Such compounds are useful, for example, asanalytical tools or probes in biological assays.

Description of Compounds of the Invention

The present invention relates to a compound of formula I:

-   or a pharmaceutically acceptable salt thereof, wherein-   R³ is H, Cl or F;-   X¹ is N or CR⁴;-   R² is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH₂, CONHR′, CON(R′)₂,    or CN;-   R⁴ is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH₂, CONHR′, CON(R′)₂,    or CN;-   or R² and R⁴, taken together, form a 5-7 membered aryl or heteroaryl    ring optionally substituted with 1-4 occurrences of R¹⁰;-   R′ is a C₁₋₃ aliphatic optionally substituted with 1-4 occurrences    of R⁵;-   each R⁵ is independently selected from halogen, CF₃, OCH₃, OH, SH,    NO₂, NH₂, SCH₃, NCH₃, CN or unsubstituted C₁₋₂ aliphatic, or two R⁵    groups, together with the carbon to which they are attached, form a    cyclopropyl ring or C═O;-   each R¹⁰ is independently selected from halogen, OCH₃, OH, NO₂, NH₂,    SH, SCH₃, NCH₃, CN or unsubstituted C₁₋₂aliphatic;-   R¹ is

-   R″ is H or is a —C₁₋₂ aliphatic optionally substituted with 1-3    occurrences of R″;-   each R¹¹ is independently selected from halogen, OCH₃, OH, SH, NO₂,    NH₂, SCH₃, NCH₃, CN, CON(R¹⁵)₂ or unsubstituted C₁₋₂ aliphatic, or    two R¹¹ groups, together with the carbon to which they are attached,    form a cyclopropyl ring or C═O;-   R⁶ is a C₁₋₄ aliphatic optionally substituted with 1-5 occurrences    of R¹²;-   each R¹² is independently selected from halogen, OCH₃, OH, NO₂, NH₂,    SH, SCH₃, NCH₃, CN or unsubstituted C₁₋₂aliphatic, or two R¹²    groups, together with the carbon to which they are attached, form a    cyclopropyl ring;-   Ring A is a 4-8 membered saturated nitrogen-containing ring    comprising up to two additional heteroatoms selected from N, O or S    and optionally substituted with 1-4 occurrences of R¹³;-   each R¹³ is independently selected from halogen, R′, NH₂, NHR′,    N(R′)₂, SH, SR′, OH, OR′, NO₂, CN, CF₃, COOR′, COOH, COR′, OC(O)H,    OC(O)R′, CONH₂, CONHR′, CON(R′)₂, NHC(O)R′ or NR′C(O)R′; or any two    R¹³ groups, on the same substituent or different substituents,    together with the atom(s) to which each R¹³ group is bound, form a    3-7 membered saturated, unsaturated, or partially saturated    carbocyclic or heterocyclic ring optionally substituted with 1-3    occurrences of R⁵;-   R⁸ is C₁₋₄ aliphatic optionally substituted with 1-5 occurrences of    R¹²;-   R⁹ is C₁₋₂ alkyl; or-   R⁸ and R⁹ are taken together to form a 3-7 membered carbocyclic or    heterocyclic saturated ring optionally substituted with 1-5    occurrences of R¹²;-   R¹⁴ is H or unsubstituted C₁₋₂ alkyl;-   R¹⁵ is H or unsubstituted C₁₋₂ alkyl; and-   R⁷ is a C₂₋₃ aliphatic or cycloaliphatic optionally substituted with    up to 6 occurrences of F.

In one embodiment, a compound of the invention has one of formulae I-Aor I-B:

In one embodiment, R³ is H or Cl. In a further embodiment, R³ is Cl. Ina further embodiment, R³ is H.

In one embodiment, R² is H, F, R′, OH or OR′. In a further embodiment,R² is H or F.

In one embodiment, the compound is of formula I-A and R⁴ is H, F, R′, OHor OR′. In another embodiment, R⁴ is H or F. In a further embodiment, R⁴is F and R² is H. In another embodiment, R² is F and R⁴ is H. In anotherembodiment, R² and R⁴ are both H. In a further embodiment, R³ is Cl. Inan alternative embodiment, R³ is H.

In another embodiment, the compound is of formula I-A and R² and R⁴ aretaken together to form a 6-membered aryl ring. In a further embodiment,R³ is Cl. In an alternative embodiment, R³ is H.

In another embodiment, R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F,CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F or CH₂CH₂CHF₂. In a further embodiment,R⁷ is CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃ or CH₂CH₂CF₃. In yet a furtherembodiment, R⁷ is CH₂CF₃.

In another embodiment, R″ is H or CH₃. In a further embodiment, R″ is H.

In another embodiment, R¹⁴ is H. In yet another embodiment, R¹⁵, ifpresent, is H. In another embodiment, R¹⁵ is absent.

In another embodiment, the invention provides a compound of formula II:

wherein X^(1A) is N, CH or CF and R^(1A) is

In a further embodiment, R⁷ is CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃ or CH₂CH₂CF₃.In yet a further embodiment, R⁷ is CH₂CF₃.

In another embodiment, the invention provides a compound of formula III:

wherein X^(1A) is N, CH or CF and R^(1A) is

In a further embodiment, R⁷ is CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃ or CH₂CH₂CF₃.In yet a further embodiment, R⁷ is CH₂CF₃.

In another embodiment of any of formulae I, II or III, R⁶ is selectedfrom

In a further embodiment, R⁶ is selected from

In yet a further embodiment, R⁶ is selected from

In another embodiment of any of formulae I, II or III, Ring A is

and R^(13,) is H or R¹³.

In a further embodiment, Ring A is

In a further embodiment, Ring A is

In one embodiment, each R¹³ is independently selected from halogen, R′,NH₂, NHR′, N(R′)₂, SH, SR′, OH, OR′, NO₂, CN, CF₃, COOR′, COOH, COR′,OC(O)R′ or NHC(O)R′; or any two R¹³ groups, on the same substituent ordifferent substituents, together with the atom(s) to which each R¹³group is bound, form a 3-7 membered saturated, unsaturated, or partiallysaturated carbocyclic or heterocyclic ring optionally substituted with1-3 occurrences of R⁵.

In one embodiment of this invention, R¹³ is absent. In anotherembodiment, Ring A is substituted with one occurrence of R¹³. In afurther embodiment, the one occurrence of R¹³ is OH, CH₃, F, OR′ orNHR′. In yet a further embodiment, R′ is C₁₋₂ alkyl or C₂₋₃ alkenyl. Inanother embodiment, R¹³ is OH.

In another embodiment of any of formulae I, II or III, R⁸ and R⁹ aretaken together to form a ring selected from

wherein one or more carbon atoms in of said ring are optionally andindependently replaced by N, O or S.

In another embodiment of any of formulae I, II or III, R⁸ and R⁹ are

In a further embodiment, R⁸ and R⁹ are

In yet a further embodiment, R⁸ and R⁹ are

In still a further embodiment, R⁸ and R⁹ are

In another embodiment, the invention provides a compound of formulae I,IA, IB, II or III, wherein said compound inhibits a JAK kinase with alower K_(i) (i.e., is more potent) than said compounds inhibits one ormore kinases selected from Aurora-1 (AUR-B), Aurora-2 (AUR-A), Src,CDK2, Flt-3 or c-Kit. In another embodiment, the invention provides acompound of formulae I, IA, IB, II or III, wherein said compoundinhibits JAK3 with a lower K_(i) than said compound inhibits one or morekinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 orc-Kit.

In another embodiment, the invention provides a compound of any offormulae I, IA, IB, II or III, wherein said compound inhibits JAK3 witha K_(i) of less than 0.1 μM. In a further embodiment, the inventionprovides a compound of any of formulae I, IA, IB, II or III, whereinsaid compound inhibits JAK3 with a K_(i) of less than 0.01 μM. Inanother embodiment, the invention provides a compound of any of formulaeI, IA, IB, II or III, wherein said compound inhibits JAK3 with a K_(i)of less than 0.01 μM and inhibits Aurora-2 with a K_(i) that is at least5-fold higher than the K_(i) of JAK3. In a further embodiment, theinvention provides a compound of any of formulae I, IA, IB, II or III,wherein said compound inhibits JAK3 with a K_(i) of less than 0.01 μMand inhibits Aurora-2 with a K_(i) that is at least 10-fold higher thanthe K_(i) of JAK3.

In another embodiment, the invention provides a compound of formulae I,IA, IB, II or III, wherein said compound inhibits JAK3 in a cellularassay with an IC₅₀ of less than 5 μM. In a further embodiment, saidcompound inhibits JAK3 in a cellular assay with an IC₅₀ of less than 1μM.

In another embodiment, said compound inhibits JAK3 in a cellular assaywith an IC₅₀ that is at least 5-fold less than said compound inhibitsone or more kinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2,Flt-3 or c-Kit in a cellular assay. In another embodiment, the inventionprovides a compound of formulae I, IA, IB, II or III, wherein saidcompound inhibits JAK3 in a cellular assay with an IC₅₀ of less than 5μM, wherein the IC₅₀ of JAK2 is at least 5-fold higher than the IC₅₀ ofJAK3. In a further embodiment, said compound inhibits JAK3 in a cellularassay with an IC₅₀ of less than 1 μM, wherein the IC₅₀ of JAK2 is atleast 5-fold higher than the IC₅₀ of JAK3. In a further embodiment, saidcompound inhibits JAK3 in a cellular assay with an IC₅₀ of less than 5μM, wherein the IC₅₀ of JAK2 is at least 10-fold higher than the IC₅₀ ofJAK3. In a further embodiment, said compound inhibits JAK3 in a cellularassay with an IC₅₀ of less than 1 μM, wherein the IC₅₀ of JAK2 is atleast 10-fold higher than the IC₅₀ of JAK3. In yet a further embodiment,the invention provides a compound of formulae I, IA, IB, II or III,wherein said compound inhibits JAK3 in a cellular assay with an IC₅₀ ofless than 1 μM, wherein the IC₅₀ of JAK2 is at least 5-fold higher thanthe IC₅₀ of JAK3, and wherein said compound inhibits JAK3 with a K_(i)of less than 0.01 μM and inhibits Aurora-2 with a K_(i) that is at least5-fold higher than the K_(i) of JAK3. In yet a further embodiment, saidcompound inhibits JAK3 in a cellular assay with an IC₅₀ of less than 1μM, wherein the IC₅₀ of JAK2 is at least 10-fold higher than the IC₅₀ ofJAK3, and wherein said compound inhibits JAK3 with a K_(i) of less than0.01 μM and inhibits Aurora-2 with a K_(i) that is at least 10-foldhigher than the K_(i) of JAK3.

In another embodiment, the invention provides a compound of Table 1,Table 2 or Table 3:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

TABLE 2

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

TABLE 3

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

Uses, Formulation and Administration Pharmaceutically AcceptableCompositions

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of formulae I, IA, IB, II or III.

In a further embodiment, the composition additionally comprising atherapeutic agent selected from a chemotherapeutic or anti-proliferativeagent, an anti-inflammatory agent, an immunomodulatory orimmunosuppressive agent, a neurotrophic factor, an agent for treatingcardiovascular disease, an agent for treating destructive bonedisorders, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, oran agent for treating immunodeficiency disorders.

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in the compositions of this inventionis such that is effective to measurably inhibit a protein kinase,particularly a JAK family kinase, in a biological sample or in apatient. Preferably the composition of this invention is formulated foradministration to a patient in need of such composition. Mostpreferably, the composition of this invention is formulated for oraladministration to a patient.

The term “patient”, as used herein, means an animal, preferably amammal, and most preferably a human.

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof. As used herein, the term “inhibitorilyactive metabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a JAK family kinase.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The term “measurably inhibit”, as used herein means a measurable changein kinase activity, particularly JAK kinase activity, between a samplecomprising a compound of this invention and a JAK kinase and anequivalent sample comprising JAK kinase in the absence of said compound.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal, intraocular,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated, e.g., as micronized suspensions in isotonic, pH adjustedsterile saline or other aqueous solution, or, preferably, as solutionsin isotonic, pH adjusted sterile saline or other aqueous solution,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutically acceptablecompositions may be formulated in an ointment such as petrolatum. Thepharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compounds of the invention are preferably formulated in dosage unitform for ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

Depending upon the particular condition, or disease, to be treated orprevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, Gleevec™, adriamycin,dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan,taxol, interferons, and platinum derivatives.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Uses of the Compounds and Compositions

In one embodiment, the invention provides a method of inhibiting JAKkinase activity in a patient, comprising administering to said patient acompound or composition of the invention.

In another embodiment, the invention comprises a method of treating orlessening the severity of a JAK-mediated condition or disease in apatient. The term “JAK-mediated disease”, as used herein means anydisease or other deleterious condition in which a JAK family kinase, inparticular JAK2 or JAK3, is known to play a role. In a furtherembodiment, the invention comprises a method of treating a JAK3-mediateddisease. Such conditions include, without limitation, immune responsessuch as allergic or type I hypersensitivity reactions, asthma,autoimmune diseases such as transplant rejection, graft versus hostdisease, rheumatoid arthritis, amyotrophic lateral sclerosis, andmultiple sclerosis, neurodegenerative disorders such as familialamyotrophic lateral sclerosis (FALS), as well as in solid andhematologic malignancies such as leukemias and lymphomas.

In another embodiment, the invention provides a method of treating orlessening the severity of a disease of condition selected from aproliferative disorder, a cardiac disorder, a neurodegenerativedisorder, an autoimmune disorder, a condition associated with organtransplant, an inflammatory disorder, an immune disorder or animmunologically mediated disorder, comprising administering to saidpatient a compound or composition of the invention.

In a further embodiment, the method comprises the additional step ofadministering to said patient an additional therapeutic agent selectedfrom a chemotherapeutic or anti-proliferative agent, ananti-inflammatory agent, an immunomodulatory or immunosuppressive agent,a neurotrophic factor, an agent for treating cardiovascular disease, anagent for treating diabetes, or an agent for treating immunodeficiencydisorders, wherein said additional therapeutic agent is appropriate forthe disease being treated and said additional therapeutic agent isadministered together with said composition as a single dosage form orseparately from said composition as part of a multiple dosage form.

In one embodiment, the disease or disorder is allergic or type Ihypersensitivity reactions, asthma, diabetes, Alzheimer's disease,Huntington's disease, Parkinson's disease, AIDS-associated dementia,amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiplesclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia, stroke, baldness, transplant rejection, graftversus host disease, rheumatoid arthritis, amyotrophic lateralsclerosis, and multiple sclerosis, and solid and hematologicmalignancies such as leukemias and lymphomas. In a further embodiment,said disease or disorder is asthma. In another embodiment, said diseaseor disorder is transplant rejection. In another embodiment, said diseaseor disorder is rheumatoid arthritis.

In another embodiment, a compound or composition of this invention maybe used to treat a myeloproliferative disorder. In one embodiment, themyeloproliferative disorder is polycythemia vera, essentialthrombocythemia, or chronic idiopathic myelofibrosis. In anotherembodiment, the myeloproliferative disorder is myeloid metaplasia withmyelofibrosis, chronic myeloid leukemia (CML), chronic myelomonocyticleukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome,systematic mast cell disease, atypical CML or juvenile myelomonocyticleukemia.

In another embodiment, the invention provides for the use of a compoundof formulae I, IA, IB, II or III to treat a JAK-mediated disease. In afurther embodiment, the invention provides for the use of said compoundto treat any of the diseases discussed above. In another embodiment, theinvention provides for the use of a compound of formulae I, IA, IB, IIor III for the manufacture of a medicament for treating a JAK-mediateddisease. In a further embodiment, the invention provides for the use ofsaid compound for the manufacture of a medicament for treating any ofthe diseases discussed above.

In another embodiment, the invention provides a method of inhibiting JAKkinase activity in a biological sample, comprising contacting saidbiological sample with a compound or composition of the invention.

The term “biological sample”, as used herein, means an ex vivo sample,and includes, without limitation, cell cultures or extracts thereof;tissue or organ samples or extracts thereof; biopsied material obtainedfrom a mammal or extracts thereof; and blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof.

Inhibition of kinase activity, particularly JAK kinase activity, in abiological sample is useful for a variety of purposes that are known toone of skill in the art. Examples of such purposes include, but are notlimited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more of theaforementioned disorders. The compounds and compositions, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of the disorder or disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike.

In an alternate embodiment, the methods of this invention comprise theadditional step of separately administering to said patient anadditional therapeutic agent. When these additional therapeutic agentsare administered separately they may be administered to the patientprior to, sequentially with or following administration of thecompositions of this invention.

The compounds of this invention or pharmaceutical compositions thereofmay also be used for coating an implantable medical device, such asprostheses, artificial valves, vascular grafts, stents and catheters.Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a compound of this invention.

Suitable coatings and the general preparation of coated implantabledevices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and5,304,121. The coatings are typically biocompatible polymeric materialssuch as a hydrogel polymer, polymethyldisiloxane, polycaprolactone,polyethylene glycol, polylactic acid, ethylene vinyl acetate, andmixtures thereof. The coatings may optionally be further covered by asuitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol,phospholipids or combinations thereof to impart controlled releasecharacteristics in the composition. Implantable devices coated with acompound of this invention are another embodiment of the presentinvention. The compounds may also be coated on implantable medicaldevices, such as beads, or co-formulated with a polymer or othermolecule, to provide a “drug depot”, thus permitting the drug to bereleased over a longer time period than administration of an aqueoussolution of the drug.

Methodology for Synthesis and Characterization of Compounds

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds or by thosemethods depicted in the Examples below. See, e.g., the examplesdescribed in WO 2005/095400, which is herein incorporated by referencein its entirety.

All references provided in the Examples are herein incorporated byreference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2nd Ed., Washington, D.C.: American ChemicalSociety, 1997, herein incorporated in its entirety by reference.

EXAMPLES Example 1 Preparation of Compounds of the Invention

Step 1

To a stirred solution of Boc-valine (1; R₁ is Me; 3.8 g, 0.02 mol), EDC(4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol)in 100 mL of DCM is added trifluoroethylamine HCl (2.92 g, 0.022 mol).The reaction mixture is stirred for 16 h. It is concentrated to drynessand redissolved in EtOAc, washed successively with 0.5N HCl, saturatedaqueous solution of NaHCO₃ and brine. The organic layer is dried(Na₂SO₄) and concentrated in vacuo to give 5.4 g (98%) of 2 as a whitesolid.

Step 2

Compound 2 (5.32 g, 0.0197 mol) is deprotected with a 1:1 mixture ofDCM/TFA at rt for 45 min. Concentration to dryness gives theintermediate amine that is used directly for the next step. A mixture of5-fluoro-2,4-dichloropyrimidine (3; R is F; 3.28 g, 0.0197 mol), thecrude amine TFA salt (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol)are stirred in isopropanol at rt for 16 h. The reaction mixture isconcentrated in vacuo and redissolved in EtOAc, washed successively with0.5N HCl, saturated aqueous solution of NaHCO₃ and brine. The organiclayer is dried (Na₂SO₄) and concentrated in vacuo to give a crude oilthat is subjected to chromatography (50% EtOAc/50% hexanes) to yield thedesired compound 4.

Step 3

A mixture of 5 (30 mg, 0.075 mmol; prepared according to WO2005/095400), 4 (23 mg, 0.075 mmol), Pd (Ph₃P)₄ (9 mg, 0.0078 mmol) andsodium carbonate 2M (115 uL, 0.23 mmol) in 1 mL of DME is microwaved at150° C. for 10 minutes. The reaction mixture is filtered through a shortpad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, afterconcentration to dryness, the crude intermediate that is used directlyfor the next step.

The crude intermediate is dissolved in 1 mL of dry methanol and 200 uLof sodium methoxide in methanol 25% was added. The reaction mixture isstirred at 60° C. for 1 h and quenched with 6N HCl (154 uL). The mixtureis dried under a flow of nitrogen and purified by reverse phase HPLC(10-60 MeCN/water w/0.5% TFA) to provide the desired material of formula6a.

Compounds of formulae 6b and 6c may be prepared in an analogous mannerusing the appropriate starting reagents. For instance, a compound offormula 6b may generally be made by substituting tert-butyl2-(2,2,2-trifluoroethylcarbamoyl) pyrrolidine-1-carboxylate for compound1, while a compound of formula 6c may generally be made by substitutingtert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)propan-2-ylcarbamate forcompound 1.

Example 2 Analytical Results

Tables 4, 5 and 6 below depicts exemplary ¹H-NMR data (NMR) and liquidchromatographic mass spectral data, reported as mass plus proton (M+H),as determined by electrospray, and retention time (RT) for certaincompounds of the present invention, wherein compound numbers in Tables4, 5 and 6 correspond to the compounds depicted in Tables 1, 2 and 3,respectively (empty cells indicate that the test was not performed):

TABLE 4 Cmpd # M + H RT NMR 1 442.90 2.20 DMSO-d6: 12.4 (br s, 1H); 8.7(dd, 1H); 8.65 (s, 1H); 8.25 (m, 2H); 8.2 (m, 1H); 4.8 (d, 1H); 4.0-3.8(m, 4H); 2.3 (m, 1H); 2.05-1.9 (m, 3H) 2 442.90 2.20 DMSO-d6: 12.4 (brs, 1H); 8.7 (dd, 1H); 8.65 (s, 1H); 8.25 (m, 2H); 8.2 (m, 1H); 4.8 (d,1H); 4.0-3.8 (m, 4H); 2.3 (m, 1H); 2.05-1.9 (m, 3H) 3 430.90 2.50(CD3OD) 1.7 (s, 6H), 3.8 (m, 2H), 8.15 (s, 1H), 8.2 (d, 1H), 8.25 (m,1H), 8.5 (t, 1H), 8.85 (d, 1H) 4 463.00 1.90 (CD3OD) 1.9 (s, 6H), 3.8(m, 2H), 7.75 (t, 1H), 7.9 (d, 1H), 8.05 (t, 1H), 8.35 (d, 1H), 8.55(d + t, 2H), 8.7 (s, 1H), 8.85 (d, 1H) 5 399.00 1.70 DMSO-d6: 8.92 (m,1H); 8.60 (m, 2H); 8.32 (s, 1H); 8.18 (m, 1H); 6.65 (m, 1H); 6.72 (m,1H); 4.80 (m, 1H); 4.00 (m, 2H); 1.42 9d, 3H) 6 417.00 2.40 DMSO-d6:8.70 (dd, 1H); 8.65 *s, 1H); 8.28 (m, 2H); 8.20 (m, 1H); 7.90 (m, 1H);4.62 (m, 1H); 3.88 (m, 2H); 1.41 (d, 3H) 7 449.00 2.10 DMSO-d6: 8.86 (m,1H); 8.76 (m, 1H); 8.55 (m, 1H); 8.40 (m, 1H); 7.96 (m, 1H); 7.85 (m,1H); 7.70 (m, 1H); 5.00 (m, 1H); 3.98 (m, 2H); 1.58 (d, 3H) 8 459.301.70 DMSO-d6: 12.3 (br s, 1H); 8.7 (s, 1H); 8.6 (t, 1H); 8.3 (m, 2H);8.2 (m, 1H); 4.75 (m, 1H); 4.4 (m, 1H); 4.05-3.7 (m, 5H); 1.9 (m, 1H) 9457.30 2.20 DMSO-d6: 12.3 (br s, 1H); 8.8 (m, 1H); 8.7 (s, 1H); 8.3 (m,2H); 8.2 (m, 1H); 4.3 (m, 1H); 4.05-3.8 (m, 4H); 2.25 (m, 1H); 2.1 (m,1H); 1.7 (m, 1H); 1.15 (m, 3H) 10 459.30 1.80 DMSO-d6: 12.35 (br s, 1H);8.8 (m, 1H); 8.65 (s, 1H); 8.25 (m, 2H); 8.15 (m, 1H); 4.6 (m, 1H); 4.3(m, 1H); 4.05 (m, 1H); 3.9-3.8 (m, 3H); 1.95 (m, 2H) 11 455.30 2.10DMSO-d6: 12.35 (br s, 1H); 8.95 (m, 1H); 8.7 (s, 1H); 8.3 (m, 2H); 8.2(m, 1H); 4.9 (m, 1H); 4.1-3.9 (m, 4H); 1.8-1.6 (m, 2H); 0.75 (m, 1H);0.4 (m, 1H) 12 459.30 1.70 DMSO-d6: 12.3 (br s, 1H); 8.7 (s, 1H); 8.6(t, 1H); 8.25 (m, 2H); 8.15 (m, 1H); 4.75 (m, 1H); 4.4 (m, 1H);4.05-3.65 (m, 5H); 1.9 (m, 1H) 13 459.30 1.70 DMSO-d6: 12.3 (br s, 1H);8.8 (m, 1H); 8.7 (s, 1H); 8.3 (m, 2H); 8.2 (m, 1H); 4.8 (m, 1H); 4.45(m, 1H); 4.05-3.65 (m, 4H); 2.25 (m, 1H); 1.9 (m, 1H) 14 425.00 1.70DMSO-d6: 12.9 (br s, 1H); 8.9 (m, 1H); 8.6 (m, 2H); 8.4 (s, 1H); 8.35(m, 1H); 6.7 (m, 1H); 4.9 (m, 1H); 4.1-3.9 (m, 2H); 3.8 (m, 1H); 3.65(m, 1H); 2.4 (m, 1H); 2.15-1.95 (m, 3H) 15 461.30 2.10 16 425.00 1.70DMSO-d6: 12.9 (br s, 1H); 8.85 (m, 1H); 8.6 (m, 2H); 8.35 (s, 1H); 8.3(m, 1H); 6.7 (m, 1H); 4.9 (m, 1H); 4.1-3.9 (m, 2H); 3.75 (m, 1H); 3.6(m, 1H); 2.4 (m, 1H); 2.15-1.95 (m, 3H) 17 461.30 2.20 18 427.20 1.90DMSO d6: 13.0 ppm (bs, 1H), 9.0 (t, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.4(s, 1H), 8.2 (d, 1H), 6.8 (bs, 1H), 4.8 (t, 1H), 4.1 (m, 1H), 3.8 (m,2H), 2.3 (m, 1H), 1.05 (d, 3H), 1.0 (d, 3H) 19 441.20 2.00 DMSO d6: 13.0ppm (bs, 1H), 9.0 (t, 1H), 8.7 (s, 2H), 8.4 (s, 1H), 8.1 (d, 1H), 6.6(d, 1H), 4.8 (t, 1H), 3.8-4.2 (m, 4H), 1.7 (bs, 2H), 1.0 (d, 3H), 0.9(d, 3H) 20 445.20 2.90 DMSO d6: 12.4 ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s,1H), 8.3 (s, 1H), 8.2 (d, 2H), 7.6 (d, 1H), 4.5 (t, 1H), 3.9-4.1 (m,2H), 2.2 (m, 1H), 1.0 (d, 3H), 0.9 (d, 3H) 21 459.20 3.00 DMSO d6: 12.4ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s, 1H), 8.3 (m, 3H), 7.8 (d, 1H), 4.7(t, 1H), 3.9 (m, 2H), 1.9 (m, 1H), 1.8 (m, 1H), 1.6 (m, 1H), 1.0 (d,3H), 0.9 (d, 3H) 22 473.20 3.40 DMSO d6: 8.7 ppm (t, 1H), 8.6 (s, 1H),8.4 (s, 1H), 8.35 (s, 1H), 8.3 (s, 1H), 7.9 (d, 1H), 4.7 (t, 1H), 4.0(m, 2H), 3.9 (s, 3H), 1.9 (m, 1H), 1.8 (m, 1H), 1.7 (m, 1H), 1.0 (d,3H), 0.9 (d, 3H) 23 431.10 2.50 DMSO d6: 12.4 (bs, 1H), 8.8 (t, 1H), 8.7(s, 1H), 8.3 (s, 1H), 8.25 (dd, 2H), 7.7 (bs, 1H), 4.5 (q, 1H), 3.8-4.0(m, 2H), 1.9 (q, 2H), 1.0 (t, 3H) 24 413.10 1.80 DMSO d6: 12.9 ppm (bs,1H), 9.0 (t, 2H), 8.65 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.1 (d, 1H),6.7 (bs, 1H), 4.7 (m, 1H), 3.8-4.2 (m, 2H), 1.9 (m, 2H), 1.0 (t, 3H) 25439.20 2.00 1H NMR (CD3OD, 500 MHz): 1.53-2.05 (m, 6H), 2.45-2.53 (m,1H), 3.46-3.59 (m, 1H), 3.83-4.32 (m, 3H), 7.06 (s, br., 1H), 8.18 (d,1H), 8.38 (d, 1H), 8.42 (s, 1H), 8.83 (s, br., 1H) 26 457.10 3.20 1H NMR(CD3OD, 500 MHz): 1.57-2.03 (m, 6H), 2.37-2.44 (m, 1H), 3.50-3.57 (m,1H), 3.90-4.09 (m, 2H), 4.49-4.57 (m, 1H), 5.38 (s, br., 1H), 8.26 (s,1H), 8.28 (d, 1H), 8.31 (d, 1H), 8.60 (d, 1H) 27 429.30 2.30 (CD3OD) 1.3(m, 2H), 1.8 (m, 2H), 3.9 (m, 2H), 8.25 (m, 3H), 8.6 (t, 1H), 8.8 (d,1H) 28 439.20 1.90 DMSO d6: 13.0 ppm (bs, 1H), 9.0 (s, 1H), 8.7 (s, 1H),8.6 (s, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 6.7 (s, 1H), 4.9 (d, 1H), 3.9-4.1(m, 3H), 1.9 (q, 1H), 1.6 (q, 1H), 0.9 (bs, 1H), 0.5 (m, 2H), 0.2 (m,2H) 29 457.10 2.80 DMSO d6: 12.4 ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s, 1H),8.3 (s, 1H), 8.25 (m, 2H), 7.8 (bs, 1H), 4.7 (q, 1H), 3.8-4.0 (m, 3H),1.9 (m, 1H), 1.6 (m, 1H), 0.9 (m, 1H), 0.4 (m, 2H), 0.2 (m, 2H) 30459.10 1.90 DMSO d6: 12.9 ppm (bs, 1H), 9.0 (s, 1H), 8.7 (s, 1H), 8.6(s, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 6.7 (s, 1H), 4.9 (s, 1H), 3.9-4.1 (m,2H), 2.5-2.7 (m, 2H), 2.1 (m, 3H), 2.0 (s, 3H) 31 477.10 2.70 DMSO d6:12.4 ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s, 1H), 8.3 (s, 2H), 8.25 (s, 1H),7.9 (s, 1H), 4.8 (q, 1H), 3.8-4.0 (m, 2H), 2.5-2.7 (m, 2H), 2.2 (m, 2H),2.1 (s, 3H) 32 458.10 1.90 (d4-methanol) 8.71 (s, 1H), 8.24 (d, 1H),8.20 (s, 1H), 8.15 (s, 1H), 5.11 (br s, 1H), 4.32 (d, 1H), 4.01-3.55 (m,4 H), 3.17 (dd, 1H), 3.11-2.95 (m, 2H) 33 440.10 1.40 (d4-methanol) 8.72(d, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.21 (d, 1H), 6.65 (d, 1H), 5.25(br s, 1H), 4.12-3.87 (m, 3 H), 3.57 (d, 1H), 3.44 (dd, 1H), 3.14-2.82(m, 3H) 34 457.00 3.00 DMSO-d6: 12.4 (s, 1H); 8.65 (s, 1H); 8.35-8.25(m, 3H); 8.1 (s, 1H); 3.95-3.8 (m, 2H); 3.7 (m, 2H); 2.05 (m, 4H); 1.65(s, 3H). 35 483.10 2.80 36 469.10 2.50 DMSO d6 12.5 (bs, 1H); 9.0 (m,1H); 8.7 (m, 3H); 8.3 (m, 1H); 4.8 (bs, 1H); 4.0-3.5 (m, 4); 2.3 (m,1H); 2.0 (m, 3H) 37 411.10 2.10 1H NMR (CD3OD, 500 MHz): 2.42-2.52 (m,1H), 2.80-2.93 (m, 1H), 3.89-4.14 (m, 2H), 4.27-4.37 (m, 2H), 5.09-5.16(m, 1H), 7.34 (d, 1H), 8.18 (d, 1H), 8.30 (s, 1H), 8.50 (s, 1H), 8.66(s, 1H) 38 459.10 2.90 1H NMR (CD3OD, 500 MHz): 3.46-3.69 (m, 2H),3.88-4.04 (m, 3H), 4.13-4.52 (m, 3H), 4.83-4.90 (m, 1H), 6.47 (d, 1H),7.44 (d, 1H), 8.00 (d, 1H), 8.14 (d, 1H), 8.27-8.35 (m, 2H), 8.68 (s,1H) 39 458.10 1.80 (d4-methanol) 8.74 (d, 1H), 8.42 (d, 1H), 8.25 (s,1H), 8.23 (d, 1H), 5.62 (br s, 1H), 4.62 (d, 1H), 4.04-3.95 (m, 3H),3.66 (ddd, 1H), 3.46 (dd, 1H), 3.41-3.34 (m, 2H) 40 440.10 1.40(d4-methanol) 8.72 (d, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.21 (d, 1H),6.65 (d, 1H), 5.26 (br s, 1H), 4.10-2.84 (m, 8H) 41 525.10 2.70(d4-methanol) 8.72 & 8.70 (2d, 1H), 8.31 & 8.27 (2d, 1H), 8.21 (d, 1H),8.18 & 8.14 (2s, 1H), 7.35, 7.24 (2d, 1H), 5.36 (br s, 1H), 4.51-3.52(m, 10 H) 42 508.10 1.80 (d4-methanol) 8.73 & 8.70 (2d, 1H), 8.36 & 8.33(2d, 1H), 8.25 (s, 1H), 8.22 (d, 1H), 6.73, 6.61 (2d, 1H), 5.50, 5.22 (2br s, 1H), 4.51-3.51 (m, 10 H) 43 427.10 1.90 DMSO d6: 13.0 ppm (bs,1H), 9.0 (s, 1H), 8.6 (d, 2H), 8.4 (s, 1H), 8.2 (d, 1H), 6.7 (s, 1H),4.8 (s, 1H), 3.8-4.2 (m, 3H), 1.9 (m, 2H), 1.4-1.5 (m, 2H), 0.9 (t, 3H)44 445.10 2.70 DMSO d6: 12.4 ppm (s, 1H), 8.8 (t, 1H), 8.7 (s, 1H), 8.3(m, 3H), 7.8 (bs, 1H), 4.6 (q, 1H), 3.8-4.0 (m, 2H), 1.8 (m, 2H), 1.3-1.5 (m, 2H), 0.9 (t, 3H) 45 425.10 2.20 DMSO-d6: 12.45 (s, 1H); 8.65 (s,1H); 8.5 (m, 1H); 8.3 (m, 2H); 8.2 (m, 1H); 5.9 (t, 1H); 4.8 (d, 1H);4.0 (m, 1H); 3.85 (m, 1H); 3.6-3.4 (m, 2H); 2.25 (m, 1H); 2.0 (m, 3H) 46443.10 2.50 DMSO 1.9 (m, 2H), 2.3 (q, 2H), 2.75 (bq, 2H), 3.8 (m, 2H), 8(d, 1H), 8.15 (overlap bt, bs, 2H), 8.25 (s, 1H), 8.3 (d, 1H), 8.7 (s,1H), 12.3 (bs, 1H) 47 407.10 1.60 DMSO-d6: 13.0 (br s, 1H); 8.7-8.6 (m,3H); 8.4 (m, 1H); 8.3 (m, 1H); 6.75 (d, 0.7H); 6.3 (d, 0.3H); 5.9 (t,1H); 4.9 (d, 0.7H); 4.65 (0.3H); 4.05-3.6 (m, 2H); 2.35 (m, 1H); 2.05(m, 3H). 48 413.10 1.70 (CD3OD) 1.75 (s, 6H), 3.85 (m, 2H), 6.75 (d,1H), 8.05 (d, 1H), 8.3 (d, 1H), 8.5 (d, 1H), 8.65 (bt, 1H), 8.8 (s, 1H)49 389.10 2.00 DMSO-d6: 12.4 (br s, 1H); 8.65 (s, 1H); 8.3 (m, 2H); 8.25(m, 1H); 8.05 (m, 1H); 4.7 (d, 1H); 3.95 (m, 1H); 3.8 (m, 1H); 3.5 (m,1H); 3.1 (m, 1H); 2.25 (m, 1H); 2.0 (m, 3H); 0.95 (m, 3H) 50 457.10 2.70H NMR (500 MHz, Methanol-d4) 8.76 (d, J = 2.3 Hz, 1H), 8.48 (t, J = 6.2Hz, 1H), 8.31-8.29 (m, 3H), 3.82 (m, 2H), 3.31 (qn, Methanol-d4),2.55-2.53 (m, 2H), 2.27-2.24 (m, 2H), 1.88 (m, 4H) 51 471.10 3.07 52371.20 1.50 DMSO-d6: 13.0 (s, 1H); 8.75-8.6 (m, 2H); 8.4 (m, 1H); 8.3(m, 1H); 8.2 (m, 1H); 6.75 (d, 0.7H) 6.35 (d, 0.3H); 4.85 (d, 0.7H);4.55 (d, 0.3H); 3.8-3.6 (m, 2H); 3.2-3.0 (m, 2H); 2.35 (m, 1H); 2.05 (m,3H); 1.05 (dd, 0.7H); 0.95 (dd, 2.3H) 53 439.20 1.80 DMSO-d6: 12.85 (brs, 1H); 8.7 (s, 1H); 8.5 (s, 1H); 8.4-8.35 (m, 2h); 8.3 (d, 1H); 6.7 (m,1h); 3.95-3.7 (m, 4H); 2.15 (m, 4H); 1.7 (s, 3H) 54 456.80 2.95 DMSO-d6:12.25 (br s, 1H); 8.7 (s, 1H); 8.3 (m, 3H); 8.0 (m, 1H); 4.1-3.7 (m,4H); 2.05 (m, 4H); 1.6 (s, 3H) 55 439.20 1.80 DMSO-d6: 12.85 (br s, 1H);8.7 (s, 1H); 8.5 (s, 1H); 8.4-8.35 (m, 2h); 8.3 (d, 1H); 6.7 (m, 1h);3.95-3.7 (m, 4H); 2.15 (m, 4H); 1.7 (s, 3H) 56 469.10 2.00 DMSO-d6: 9.30(m, 1H); 8.70 (s, 1H); 8.35 (m, 1H); 8.28 (m, 2H); 4.75 (m, 1H); 3.40(m, 2H); 2.25 (m, 2H); 2.00 (m, 4H) 57 497.10 2.70 DMSO-d6: 8.80 (m,2H); 8.55 (s, 1h); 8.28 (m, 2H); 4.80 (m, 1H); 4.24 (m, 2H); 3.80 (m,4H); 2.20 (m, 1H); 1.90 (m, 23H); 1.20 (t, 2H) 58 441.10 2.00 H NMR (500MHz, DMSO-d6) 12.9 (bs, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H),8.41 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 6.2 Hz, 1H), 6.80 (s, 1H), 4.81(s, 1H), 4.11-4.06 (m, 1H), 3.87 (m, 2H), 2.00 (s, 1H), 1.66 (s, 1H),1.27- 1.21 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H)59 459.10 3.10 H NMR (500 MHz, DMSO-d6) 12.40 (s, 1H), 8.80 (t, J = 6.3Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.29 (s,1H), 8.27 (d, 1H), 7.58 (d, J = 6.2 Hz, 1H), 4.57 (t, J = 8.0 Hz, 1H),4.04-3.98 (m, 1H), 3.89-3.83 (m, 1H), 2.05- 1.99 (m, 1H), 1.65-1.60 (m,1H), 1.33-1.23 (m, 1H), 0.96 (d, 3H), 0.88 (t, 3H) 60 441.10 2.00 H NMR(500 MHz, DMSO-d6) 13.0 (bs, 1H), 8.98 (s, 1H), 8.66 (s, 1H), 8.62 (s,1H), 8.41 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 6.3 Hz, 1H), 6.84 (s, 1H),4.90 (s, 1H), 4.08-4.07 (m, 1H), 3.88 (m, 2H), 2.11-2.08 (m, 1H), 1.50(t, J = 6.9 Hz, 1H), 1.27 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.92 (q, J= 7.5 Hz, 3H) 61 459.10 3.10 H NMR (500 MHz, DMSO-d6) 12.38 (s, 1H),8.76 (t, J = 6.3 Hz, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.28 (m, J = 4.2 Hz,3H), 8.28 (s, 1H), 7.36 (d, J = 5.7 Hz, 1H), 4.72 (t, 1H), 4.02-3.85 (m,2H), 2.05 (q, J = 6.8 Hz, 1H), 1.54-1.49 (m, 1H), 1.27-1.21 (m, 1H),0.99 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H) 62 441.10 2.00 H NMR(500 MHz, DMSO-d6) 13.01 (s, 1H), 9.05 (s, 1H), 8.78 (s, 1H), 8.64 (s,1H), 8.42 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 6.4 Hz, 1H), 6.91 (s, 1H),4.89 (d, J = 8.0 Hz, 1H), 4.15-4.07 (m, 1H), 3.82-3.85 (m, 1H), 1.08 (s,9H) 63 459.10 3.30 H NMR (500 MHz, DMSO-d6) 12.41 (s, 1H), 8.85 (t, J =6.3 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.31 (d, 1H), 8.29 (s, 2H), 6.86(d, J = 7.8 Hz, 1H), 4.77 (d, J = 8.8 Hz, 1H), 4.09-4.02 (m, 1H),3.88-3.82 (m, 1H), 1.08 (s, 9H) 64 429.10 2.39 1H NMR (CD3OD, 500 MHz):2.45-2.52 (m, 1H), 2.91-3.00 (m, 1H), 3.89-4.14 (m, 2H), 4.50-4.61 (m,2H), 5.25-5.30 (m, 1H), 8.23- 8.30 (m, 3H), 8.63 (s, 1H) 65 373.40 1.90DMSO-d6: 12.9 (br s, 1H); 8.7 (s, 1H); 8.6 (s, 1H); 8.4 (s, 1H); 8.3 (s,1H); 8.15 (m, 1H); 6.8 (s, 1H); 4.6 (s, 1H); 3.1 (m, 1H); 2.7 (m, 1H);2.25 (m, 1H); 1.1-0.95 (m, 9H) 66 425.10 2.20 H NMR (500 MHz,Methanol-d4) 8.73 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.35(d, J = 2.1 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H),3.85 (m, 2H), 3.01-2.97 (m, 2H), 2.44-2.39 (m, 2H), 2.16 (m, 2H) 67409.20 1.80 DMSO-d6: 13.0 (br s, 1H); 8.75 (m, 1H); 8.65 (s, 1H); 8.6(s, 1H); 8.4 (s, 1h); 8.15 (d, 1H); 6.8 (m, 1h); 6.05 (t, 1H); 4.75 (m,1H); 3.75-3.5 (m, 2H); 2.25 (m, 1H); 1.1-0.95 (m, 6H) 68 456.60 3.83 1HNMR (CD3OD, 500 MHz): 1.68-2.00 (m, 6H), 2.26-2.33 (m, 1H), 3.49-3.58(m, 1H), 3.84-4.02 (m, 2H), 4.45-4.53 (m, 1H), 5.36-5.42 (m, 1H), 6.71(d, 1H), 8.11-8.39 (m, 4H), 8.86-8.92 (m, 1H) 69 497.80 1.79 1H NMR(CD3OD, 500 MHz): 3.38-4.35 (m, 10H), 4.67 (d, 1H), 5.19-5.54 (m, 1H),6.80-7.07 (m, 1H), 8.23-8.80 (m, 4H) 70 525.80 2.08 1H NMR (CD3OD, 500MHz): 1.29 (d, 6H), 3.43-4.30 (m, 7H), 4.68 (d, 1H), 4.86-4.94 (m, 1H),5.44 (s, br., 1H), 7.01 (s, br., 1H), 8.23-8.58 (m, 4H) 71 523.80 2.051H NMR (CD3OD, 500 MHz): 3.40-4.30 (m, 7H), 4.53-4.74 (m, 3H), 5.19-5.54(m, 3H), 5.92-6.01 (m, 1H), 6.98 (s, br., 1H), 8.24-8.57 (m, 4H) 72459.50 2.99 10.5 (s, 1H), 8.74 (d, 1H), 8.39 (s, 1H), 8.35 (d, 1H), 8.28(d, 1H), 7.20 (m, 1H), 6.73 (s, 1H), 4.5-4.8 (s, 6H), 3.98 (m, 1H), 3.68(m, 1H), 2.32 (m, 1H), 1.70 (s, 3H), 1.08 (dd, 6H) (CD3CN) 73 441.201.80 74 429.10 1.60 H NMR (500 MHz, DMSO-d6) 12.95 (bs, 1H), 8.78 (s,1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.17 (d, J =4.8 Hz, 1H), 6.90 (s, 1H), 5.30 (s, 1H), 4.74 (s, 1H), 4.21 (s, 1H),4.04-3.80 (m, 2H), 1.21 (d, J = 5.7 Hz, 3H) 75 423.00 1.80 H NMR (500MHz, DMSO-d6) 12.95 (bs, 1H), 9.07(s, 1H), 8.63 (s, 1H), 8.60 (s, 1H),8.40 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 6.75 (s, 1H), 4.99 (s, 1H),4.05-3.83 (m, 2H), 2.98 (t, J = 2.4 Hz, 1H), 2.80 (d, J = 7.3 Hz, 2H) 76429.10 1.60 H NMR (500 MHz, DMSO-d6) 12.96 (s, 1H), 8.79 (s, 1H), 8.65(s, 1H), 8.61 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.20-8.17 (m, 1H), 6.91(s, 1H), 5.25 (bs, 1H), 4.75 (s, 1H), 4.21 (s, 1H), 4.04-3.88 (m, 2H),1.22 (d, J = 6.2 Hz, 3H) 77 482.40 1.69 1H NMR (CD3OD, 500 MHz): 2.08(s, 3H), 3.18-4.97 (m, 9H), 6.87-7.08 (m, 1H), 8.24- 8.59 (m, 4H) 78518.40 1.83 1H NMR (CD3OD, 500 MHz): 2.93 (s, 3H), 3.18-4.97 (m, 9H),7.00-7.10 (m, 1H), 8.26- 8.56 (m, 4H) 79 526.50 2.00 1H NMR (CD3OD, 500MHz): 0.98 (t, 3H), 1.67-1.74 (m, 2H), 3.18-4.90 (m, 11H), 6.86-7.00 (m,1H), 8.24-8.59 (m, 4H) 80 540.50 2.12 1H NMR (CD3OD, 500 MHz): 0.97 (d,6H), 1.91-2.01 (m, 1H), 3.18-4.90 (m, 11H), 6.86-7.00 (m, 1H), 8.24-8.59(m, 4H) 81 482.50 1.61 1H NMR (CD3OD, 500 MHz): 2.08 (s, 3H), 3.18-4.97(m, 9H), 6.87-7.08 (m, 1H), 8.24- 8.59 (m, 4H) 82 518.40 1.82 1H NMR(CD3OD, 500 MHz): 2.93 (s, 3H), 3.18-4.97 (m, 9H), 7.00-7.10 (m, 1H),8.26- 8.56 (m, 4H) 83 441.20 1.50 DMSO-d6: 12.85 (br s, 1H); 9.05 (s,0.3H); 8.9 (s, 0.7H); 8.7 (m, 0.3H); 8.65-8.5 (m, 1.7H); 8.4-8.25 (m,2H); 6.75 (m, 0.7H); 6.2 (m, 0.3H); 4.9 (m, 0.7H); 4.7 (m, 0.3H); 4.5(m, 1H); 4.05-3.5 (m, 5H); 2.05 (m, 1H) 84 473.10 2.20 DMSO-d6: 12.35(br s, 1H); 8.7 (s, 1H); 8.35- 8.1 (m, 4H); 6.4 (m, 1H); 4.7 (dd, 1H);4.0 (m, 2H); 3.8 (m, 2H); 3.15 (m, 1H); 2.25 (m, 1H); 2.0 (m, 3H) 85459.10 2.00 DMSO-d6: 12.3 (br s, 1H); 8.8 (s, 1H); 8.7 (m, 1H); 8.3 (m,2H); 8.15 (m, 1H); 4.85 (m, 1H); 4.45 (m, 1H); 4.05-3.7 (m, 5H); 1.9 (m,1H) 86 413.20 2.30 H NMR (500 MHz, DMSO) 12.63 (s, 1H), 8.87-8.86 (bs,1H), 8.61 (m, 2H), 8.35-8.31 (m, 2H), 7.25 (d, J = 4.8 Hz, 1H), 5.39 (q,J = 7.1 Hz, 1H), 3.95-3.81 (m, 2H), 3.18 (s, 3H), 1.43 (d, J = 6.9 Hz,3H) 87 431.20 2.70 H NMR (500 MHz, DMSO) 12.38 (s, 1H), 8.70-8.65 (m,2H), 2H) 8.32 (d, J = 6.9 Hz, 1H), 8.29 (dd, J = 2.4, 2.8 Hz, 2H), 5.16(q, J = 7.0 Hz, 1H), 3.95-3.86 (m, 2H), 3.17 (d, J = 4.2 Hz, 3H), 1.46(d, J = 7.0 Hz, 3H) 88 400.10 2.30 DMSO-d6: 12.6 (m, 1H); 8.60 (m, 1H);8.50 (m, 1H); 8.30 (m, 1H); 8.25 (m, 1H); 4.50 (m, 1H); 3.80 (m, 2H);1.42 (m, 3H) 89 441.20 2.10 H NMR (500 MHz, DMSO) 12.41 (s, 1H), 8.78(t, J = 6.3 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.36 (d, 1H), 8.33 (d,1H), 8.30 (d, J = 2.4 Hz, 1H), 4.86 (d, J = 10.4 Hz, 1H), 3.98- 3.88 (m,2H), 3.20 (d, J = 4.9 Hz, 3H), 2.44- 2.40 (m, 1H), 1.04 (d, J = 6.5 Hz,3H), 0.90 (d, J = 6.7 Hz, 3H) 90 459.10 3.40 H NMR (500 MHz, DMSO) 12.98(s, 1H), 8.87 (bs, 1H), 8.70 (s, 2H), 8.42 (d, 1H), 8.38 (d, 1H), 5.4(bs, 1H), 3.97-3.89 (m, 2H), 3.14 (bs, 3H), 2.51-2.42 (m, 1H), 1.03 (bs,3H), 0.86 (d, J = 6.7 Hz, 3H) 91 459.40 2.95 10.95 (s, 1H), 8.68 (s,1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.28 (d, 1H), 7.25 (m, 2H), 4.1-4.5 (s,8H), 3.95 (m, 1H), 3.69 (m, 1H), 2.39 (m, 1H), 1.72 (s, 3H), 1.09 (dd,6H) (CD3CN) 92 445.40 2.70 10.69 (s, 1H), 8.70 (d, 1H), 8.48 (s, 1H),8.41 (d, 1H), 8.28 (d, 1H), 7.34 (s, 1H), 7.23 (m, 1H), 3.75-4.2 (m,26H), 2.20 (m, 2H), 1.72 (s, 3H), 0.93 (t, 3H) (CD3CN) 93 487.30 2.10DMSO-d6: 12.3 (br s, 1H); 8.85 (s, 1H); 8.65 (s, 1H); 8.3 (m, 2H); 8.15(s, 1H); 4.75 (dd, 1H); 4.25 (m, 1H); 4.05-3.8 (m, 4H); 3.6-3.45 (m,3H); 2.0 (m, 1H); 1.1 (dd, 3H) 94 499.40 2.20 95 469.40 1.90 DMSO-d6:12.3 (br s, 1H); 9.1-8.3 (m, 5H); 6.75 (m, 0.7H); 6.2 (m, 0.3H); 4.85(m, 0.7H); 4.6 (m, 0.3H); 4.3 (m, 1H); 4.1-3.5 (m, 7H); 2.1 (m, 1H); 1.1(dd, 3H) 96 481.40 2.00 97 426.10 2.51 DMSO-d6: 12.6 (m, 1H); 8.82 (m,0.5H); 8.75 (s, 0.5H); 8.62 (m, 1H); 8.58 (s, 0.5H); 8.48 (m, 1H); 8.38(m, 0.5H); 8.35 (m, 0.5H); 8.22 (m, 0.5H); 4.65-4.55 (m, 1H); 3.80-3.60(m, 4H); 2.25 (m, 1H); 1.90 (m, 3H) 98 414.10 2.52 DMSO-d6: 12.6 (m,1H); 8.95 (s, 0.5H); 8.70 (m, 0.5H); 8.50 (m, 0.5H); 8.40 (0.5H); 8.20(m, 2.0H); 8.10-7.90 (m, 1H) 99 427.10 1.80 H NMR (500 MHz, DMSO-d6)13.07 (s, 1H), 9.17 (s, 1H), 8.69-8.66 (m, 3H), 8.61 (m, 1H), 8.39 (d, J= 2.2 Hz, 1H), 8.20 (d, J = 7.1 Hz, 1H), 6.78 (d, J = 6.9 Hz, 1H),3.83-3.78 (m, 2H), 2.14-2.07 (m, 1H), 2.01-1.94 (m, 1H), 1.61 (s, 3H),0.88 (t, J = 7.5 Hz, 3H) 100 445.10 2.70 H NMR (500 MHz, DMSO-d6) 12.36(s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.41 (t, J = 6.4 Hz, 1H), 8.30-8.27(m, 2H), 8.11 (s, 1H), 7.53 (s, 1H), 3.85- 3.72 (m, 2H), 2.19-2.15 (m,1H), 1.99-1.95 (m, 1H), 1.55 (s, 3H), 0.81 (t, J = 7.5 Hz, 3H) 101473.21 2.55 DMSO-d6: 12.3 (br s, 1H); 8.8 (s, 1H); 8.7 (s, 1H); 8.3 (m,2H); 8.15 (m, 1H); 8.75 (m, 1H); 4.15 (m, 1H); 4.1-3.75 (m, 4H); 3.45(m, 4H); 2.0 (m, 1H) 102 487.23 2.70 DMSO-d6: 12.3 (br s, 1H); 8.8 (s,1H); 8.7 (s, 1H); 8.3 (m, 2H); 2H); 8.15 (m, 1H); 4.75 (m, 1H); 4.2 (m,1H); 4.05-4.75 (m, 4H); 3.5 (m, 3H); 2.0 (m, 1H); 1.1 (dd, 3H) 103455.10 1.70 104 500.10 1.90 105 499.10 2.90 DMSO-d6: 12.35 (br s, 1H);8.85 (s, 1H); 8.65 (s, 1H); 8.3 (m, 2H); 8.15 (m, 1H); 5.9 (m, 1H); 5.3(d, 1H); 5.15 (d, 1H); 4.8 (m, 1H); 4.3 (m, 1H); 4.05 (m, 2H); 4.0-3.8(m, 5H); 2.0 (m, 1H) 106 455.10 1.70 107 427.40 1.80 10.07 (s, 1H), 8.83(d, 1H), 8.26 (d, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.20 (m, 1H), 6.38(d, 1H), 6.00 (s, 1H), 3.88 (m, 1H), 3.77 (m, 1H), 1.95 (m, 2H), 1.57(s, 3H), 0.91 (t, 3H) (CD3CN) 108 359.40 1.65 109 395.40 1.77 110 441.401.91 10.01 (s, 1H), 8.71 (d, 1H), 8.23 (d, 1H), 8.17 (d, 1H), 8.12 (d,1H), 7.16 (m, 1H), 6.40 (d, 1H), 5.86 (s, 1H), 3.97 (m, 1H), 3.61 (m,1H), 1.53 (s, 3H), 1.02 (dd, 6H) (CD3CN) 111 414.10 2.50 DMSO-d6: 12.65(m, 1H); 8.95 (s, 0.5H); , 8.72 (m, 0.5H); 8.70 (m, 0.5H); 8.50 (m, 1H);8.48 (m, 0.5H); 8.40 (m, 0.5H); 8.30 (m, 1H); 8.28 (m, 0.5H); 8.03 (m,0.5H); 4.45 (m, 1H); 3.80 (m, 2H); 1.75 (m, 2H); 1.00 (m, 3H) 112 440.102.70 DMSO-d6: 12.68 (m, 1H); 8.98 (s, 0.5H); 8.68 (s, 0.5H); 8.58 (s,0.5H); 8.48 (s, 0.5H); 8.43 (s, 0.5H); 8.35-8.15 (m, 3.5H); 3.75 (m,2H); 2.15 (m, 2H); 2.02 (m, 2H); 1.65 (m, 4H) 113 426.10 2.60 DMSO-d6:12.55 (m, 1H); 8.95 (m, 0.5H); 8.68 (m, 0.5H); 8.62 (m, 0.5H); 8.56 (m,0.5H); 8.52 (m, 0.5H); 8.45 (m, 0.5H); 8.40 (m, 0.5H); 8.35 (m, 1H);8.22 (0.5H); 8.16 (m, 1H); 3.80 (m, 2H); 2.70 (m, 1H); 2.40 (m, 1H);2.25 (m, 2H); 1.88 (m, 2H) 114 512.10 1.80 DMSO-d6: 12.5 (bs, 1H); 8.95(bs, 1H); 8.50 (m, 2H); 8.32 (m, 2H); 6.80 (m, 1H); 4.50 (m, 1H);4.00-3.40 (m, 10H); 1.15 (t, 3H) 115 540.10 2.10 116 496.10 1.70DMSO-d6: 12.6 (m, 1H); 8.95 (m, 1H); 8.50 (m, 2H); 8.32 (m, 2H); 6.80(m, 1H); 4.50 (m, 1H); 4.00-3.40 (m, 10): 1.15 (t, 3H) 117 508.10 1.70118 522.20 1.90 119 459.30 1.70 DMSO-d6: 12.35 (br s, 1H); 8.8 (m, 1H);8.65 (s, 1H); 8.3 (m, 2H); 8.15 (m, 1H); 4.8 (m, 1H); 4.4 (m, 1H);4.05-3.7 (m, 4H); 2.3 (m, 1H); 1.95 (m, 1H) 120 441.40 1.70 DMSO-d6:12.9 (br s, 1H); 9.05 (m, 0.3H); 8.9 (m, 0.7H); 8.7-8.5 (m, 2H);8.4-8.25 (m, 2H); 6.75 (m, 0.7H); 6.2 (m, 0.3H); 4.95 (m, 0.7H); 4.7 (m,0.3H); 4.5 (m, 1H); 4.05-3.5 (m, 4H); 2.4 (m, 1H); 2.05 (m, 1H) 121425.00 2.03 10.1 (s, 1H), 8.89 (s, 1H), 8.29 (m, 3H), 7.27 (s, 1H), 6.51(d, 1H), 3.88 (m, 2H), 3.30 (s, 6H), 1.86 (m, 1H), 1.57 (m, 1H), 1.43(m, 1H), 1.19 (m, 1H) (CD3CN) 122 461.30 2.40 123 443.30 1.90 124 487.402.20 125 479.40 2.30 126 443.30 1.90 127 439.17 1.84 H NMR (500 MHz,MeOD) 8.79 (d, J = 2.3 Hz, 1H), 8.51 (t, J = 6.4 Hz, 1H), 8.48 (s, 1H),8.35 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz,1H), 3.87-3.81 (m, 2H), 2.56-2.52 (m, 2H), 2.25-2.20 (m, 2H), 1.93-1.86(m, 4H), 0.00 (TMS) 128 441.40 2.20 H NMR (500 MHz, DMSO) 8.66 (s, 1H),8.62 (s, 1H), 8.58 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 7.0Hz, 1H), 6.81 (s, 1H), 4.09-3.78 (m, 2H), 2.18-2.16 (m, 2H), 2.10 (m,2H), 0.77 (t, J = 7.4 Hz, 6H), 0.00 (TMS) 129 459.40 2.40 130 461.302.40 131 377.30 1.67 132 441.09 1.65 H NMR (500 MHz, Me0D) 8.70 (d, J =2.2 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J = 2.3 Hz, H), 8.12 (d, J = 7.2 Hz,1H), 7.59 (d, J = 8.2 Hz, 2H *0.7 equiv p-TsOH), 7.37 (d, J = 8.0 Hz,2H*0.7 equiv p-TsOH), 6.76 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 9.6 Hz,1H), 4.22 (d, J = 9.5 Hz, 1H), 4.07-4.04 (m, 2H), 3.88-3.83 (m, 2H),2.88-2.82 (m, 1H), 2.52-2.43 (m, 1H), 2.43 (s, 3H*0.7 equiv p-TsOH),0.00 (TMS) 133 443.30 2.86 134 441.16 1.50 135 455.10 1.80 DMSO-d6: 12.8(br s, 1H); 9.05-8.85 (m, 1H); 8.8-8.4 (m, 2H); 8.35 (m, 2H); 6.75 (m,0.8H); 6.2 (m, 0.2H); 4.85 (m, 0.8H); 4.6 (m, 0.2H); 4.2 (m, 1H); 4.0(m, 1H); 3.9-3.6 (m, 3H); 3.3 (s, 3H); 2.2 (m, 1H) 136 455.10 1.80DMSO-d6: 12.9 (br s, 1H); 8.75-8.25 (m, 5H); 6.75 (m, 0.8H); 8.45 (m,0.2H); 4.95 (m, 0.8H); 4.75 (m, 0.2H); 4.2 (m, 1H); 4.1-3.7 (m, 4H); 3.2(s, 3H); 2.3 (m, 1H) 137 473.10 2.00 DMSO-d6: 12.35 (br s, 1H); 8.65 (m,1H); 8.45 (dd, 1H); 8.25 (m, 2H); 8.15 (m, 1H); 4.8 (d, 1H); 4.1 (m,1H); 4.0 (m, 1H); 3.9 (m, 1H); 3.85 (m, 2H); 3.2 (s, 3H); 2.2 (m, 1H)138 397.00 1.74 (500 MHz, CD3OD) 8.57 (t, J = 6.2 Hz, 1H), 8.50 (s, 1H),8.48 (d, J = 2.6 Hz, 1H), 8.3 (d, J = 1.2 Hz, 1H), 8.05 (d, J = 7.2 Hz,1H), 6.7 (d, J = 7.2 Hz, 1H), 3.86-3.8 (m, 2H), 1.74 (s, 6H), 0 (TMS)139 445.10 3.30 H NMR (500 MHz, DMSO) 12.24 (s, 1H), 8.69 (s, 1H), 8.32(d, J = 6.9 Hz, 1H), 8.24 (m, 2H), 8.15 (s, 1H), 3.68-3.63 (m, 2H), 3.20(s, 1H), 1.51 (s, 1H) 140 427.10 1.80 H NMR (500 MHz, DMSO) 12.7 (bs,1H), 8.82 (s, 1H), 8.34-8.30 (m, 2H), 8.16 (s, 1H), 8.07 (d, J = 6.2 Hz,1H), 6.63 (d, J = 6.2 Hz, 1H), 3.77-3.70 (m, 2H), 3.06 (s, 3H), 1.56 (s,6H) 141 431.10 2.50 DMSO-d6: 12.2 (m, 1H); 8.60 (m, 1H); 8.22 (s, 1H);8.18 (s, 1H); 8.10 (s, 1H); 7.70 (m, 1H); 5.16 (m, 1H); 4.18 (m, 2H);3.3 (s, 2.5H); 2.9 (s, 0.5H); 1.35 (m, 3H) 142 413.10 1.80 DMSO-d6: 12.5(m, 1H); 8.70 (m, 1H); 8.30 (m, 2H); 8.18 (m, 2H); 6.42 (m, 1H); 5.25(m, 1H); 4.20 (m, 2H); 3.30 (s, 2.5H); 2.90 (s, 0.5H); 1.32 (m, 3H) 143413.10 1.84 144 377.10 1.70 145 395.10 1.74 146 428.10 2.00 147 411.102.00 148 497.10 2.40 149 554.00 2.20 150 498.00 1.80 DMSO-d6: 12.7 (m,1H); 8.92 (m, 1H); 8.60 (m, 1H); 8.42 (m, 1H); 8.32 (m, 1H); 8.28 (m,1H); 6.80 (m, 1H); 5.20 (m, 1H); 4.30-3.60 (m, 8H); 3.55 (m, 3H) 151512.00 1.90 DMSO-d6: 12.5 (m, 1H); 8.90 (m, 1H); 8.55 (m, 1H); 8.42 (m,1H); 8.32 (m, 1H); 8.30 (m, 1H); 6.70 (m, 1H); 5.20 (m, 1H); 4.35-3.55(m, 10H); 1.15 (t, 3H) 152 526.10 2.00 153 526.00 2.00 154 540.10 2.10155 540.10 2.10 156 532.80 3.10 DMSO-d6: 12.35 (br s, 1H); 8.9 (m, 1H);8.7 (s, 1H); 8.4-8.1 (m, 3H); 4.85 (dd, 1H); 4.35-4.1 (m, 2H); 4.0-3.7(m, 2H); 3.3 (m, 4H); 2.85 (m, 1H); 2.4 (m, 1H) 157 546.90 3.20 DMSO-d6:12.35 (br s, 1H); 8.9 (m, 1H); 8.7 (s, 1H); 8.35-8.15 (m, 3H); 4.9 (dd,1H); 4.1-3.75 (m, 4H); 3.1-2.9 (m, 5H); 2.15 (m, 1H); 1.95 (m, 2H) 158493.90 1.70 159 522.00 1.90 160 524.00 1.90 161 538.00 2.10 162 511.001.70 DMSO-d6: 12.8 (m, 1H); 8.90 (m, 1H); 8.55 z9m, 2H); 8.35 (, 2H);6.80 (m, 1H); 5.25 (, 1H); 4.20-3.60 (m, 8H); 2.62 (s, 6H) 163 525.001.80 164 560.00 2.20 165 508.00 1.80 166 443.00 1.60 DMSO-d6: 12.8 (brs, 1H); 8.95-8.65 (m, 1H); 8.65-8.45 (m, 2H); 8.4-8.25 (m, 2H); 6.75 (m,0.7H); 6.25 (m, 0.3H); 5.5 (d, 1H); 5.05 (m, 0.7H); 4.85 (m, 0.3H);4.2-3.7 (m, 4H); 2.8- 2.55 (m, 1H); 2.5-2.35 (m, 1H) 167 460.90 1.80DMSO-d6: 12.75 (br s, 1H); 9.0 (m, 1H); 8.65-8.3 (m, 4H); 6.7 (m, 1H);5.15 (m, 1H); 4.2 (m, 2H); 4.0 (m, 1H); 3.85 (m, 1H); 3.1 (m, 1H); 2.6(m, 1H) 168 443.00 1.60 DMSO-d6: 12.8 (br s, 1H); 9.2-8.9 (m, 1H);8.7-8.45 (m, 2H); 2H); 8.4-8.3 (m, 2H); 6.75 (m, 0.7H); 6.25 (m, 0.3H);5.55 (d, 1H); 5.0 (m, 0.7H); 4.8 (m, 0.3H); 4.2-3.7 (m, 4H); 2.9-2.7 (m,1H); 2.3-2.1 (m, 1H) 169 403.10 2.20 DMSO-d6: 12.45 (s, 1H); 8.7 (s,1H); 8.3 (m, 2H); 8.25 (m, 1H); 8.0 (dd, 1H); 4.7 (m, 1H); 3.95 (m, 1H);3.8 (m, 1H); 3.05 (m, 1H); 2.95 (m, 1H); 2.25 (m, 1H); 2.0 (m, 3H); 1.4(m, 2H); 0.75 (m, 3H). 170 385.10 1.70 DMSO-d6: 12.9 (br s, 1H); 8.7-8.6(m, 2H); 8.4 (m, 1H); 8.3 (m, 1H); 8.15 (m, 1H); 6.7 (d, 0.7H); 6.3 (d,0.3H); 4.85 (d, 0.7H); 4.5 (0.3H); 4.05-3.6 (m, 2H); 3.2-3.05 (m, 1H);2.9 (m, 1H); 2.35 (m, 1H); 2.05 (m, 3H); 1.5-1.3 (m, 2H); 0.8 (m, 1H);0.7 (m, 2H). 171 387.40 2.00 DMSO-d6: 12.95 (br s, 1H); 8.7 (s, 1H); 8.6(s, 1H); 8.4 (s, 1H); 8.3 (s, 1H); 8.15 (m, 1H); 6.8 (s, 1H); 4.65 (s,1H); 3.2 (m, 1H); 3.0 (m, 1H); 2.25 (m, 1H); 1.45 (m, 2H); 1.1-0.95 (m,6H); 0.85 (m, 3H). 172 457.10 2.40 DMSO-d6: 12.35 (br s, 1H); 8.7 (s,1H); 8.3-8.25 (m, 3H); 8.2 (m, 1H); 4.65 (d, 1H); 4.0 (m, 1H); 3.8 (m,1H); 3.5-3.3 (m, 2H); 2.4-2.2 (m, 3H); 2.0 (m, 3H). 173 439.20 1.70DMSO-d6: 12.9 (br s, 1H); 8.7-8.65 (m, 2H); 8.45-8.25 (m, 3H); 6.75 (d,0.8H); 6.3 (d, 0.2H); 4.85 (d, 0.8H); 4.55 (d, 0.2H); 4.05-3.55 (m, 4H);2.4-2.25 (m, 3H); 2.1-2.0 (m, 3H). 174 441.40 2.00 175 373.40 1.74 176427.30 1.87 177 401.10 2.00 DMSO-d6: 12.45 (s, 1H); 8.7 (s, 1H); 8.3 (m,2H); 8.25 (s, 1H); 8.15 (s, 1H); 4.6 (d, 1H); 3.9 (m, 1H); 3.8 (m, 1H);2.6 (m, 1H); 2.25 (m, 1H); 1.95 (m, 3H); 0.6 (m, 2H); 0.4 (m, 1H); 0.35(m, 1H). 178 383.10 1.60 DMSO-d6: 13.0 (br s, 1H); 8.65 (m, 1H); 8.6 (s,1H); 8.4 (m, 1H); 8.35-8.2 (m, 2H); 6.75 (d, 0.7H); 6.3 (d, 0.3H); 4.8(d, 0.7H); 4.5 (0.3H); 4.05-3.6 (m, 2H); 2.7-2.55 (m, 1H); 2.35 (m, 1H);2.05 (m, 3H); 0.7-0.2 (m, 4H). 179 385.40 1.90 DMSO-d6: 12.95 (br s,1H); 8.7 (s, 1H); 8.6 (s, 1H); 8.4 (s, 1H); 8.35 (s, 1H); 8.15 (m, 1H);6.8 (s, 1H); 4.6 (s, 1H); 2.7 (m, 1H); 2.25 (m, 1H); 1.05-0.95 (m, 6H);0.65 (m, 2H); 0.45 (m, 2H). 180 371.40 1.65

TABLE 5 Cmpd # M + H RT NMR 181 473.1 1.9 182 415.1 1.8 (500 MHz, DMSO)12.22 (s, 1H), 8.42 (dd, J = 2.8, 9.9 Hz, 1H), 8.37 (t, J = 6.4 Hz, 1H),8.26- 8.25 (m, 2H), 8.10 (d, J = 2.5 Hz, 1H), 3.78-3.71 (m, 2H), 1.57(s, 6H), 0.00 (TMS) 183 361.1 1.6 (500 MHz, DMSO) 12.27 (s, 1H), 8.47(dd, J = 2.8, 9.8 Hz, 1H), 8.25 (d, J = 3.0 Hz, 2H), 8.19 (d, J = 2.2Hz, 1H), 7.75 (t, J = 5.6 Hz, 1H), 7.56 (bs, 1H), 3.02-2.99 (m, 2H),1.56 (s, 6H), 0.77 (t, J = 7.1 Hz, 3H), 0.00 (TMS) 184 379.1 1.6 (500MHz, DMSO) 12.3 (s, 1H), 8.45 (dd, J = 2.8, 9.8 Hz, 1H), 8.25 (m, 2H),8.19 (bs, 1H), 8.05 (t, 1H), 7.7 (bs, 1H), 4.2 (dt, 2H, under water),3.2 (dq, 2H), 1.6 (s, 6H), 0.00 (TMS) 185 397.1 1.7 (500 MHz, DMSO)12.28 (s, 1H), 8.44 (dd, J = 2.8, 9.9 Hz, 1H), 8.27 (d, J = 4.4 Hz, 2H),8.19 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.69 (bs, 1H), 5.7(tt, J = 48 Hz, J = 4.3 Hz, 1H), 3.39-3.31 (m, 2H), 1.57 (s, 6H), 0.00(TMS) 186 375.1 1.7 187 361.1 2.04 188 379.1 2.21 189 343.1 2.04 190357.1 2.3 191 457 2.9 (DMSO-d6) 12.35 (s, 1H); 8.7 (d, 1H); 8.4-8.25 (m,3H); 8.1 (s, 1H); 4.1 (m, 1H); 3.95 (m, 1H); 3.85 (m, 1H); 3.7 (m, 1H);2.05 (m, 4H); 1.65 (s, 3H). 192 439 1.7 (DMSO-d6) 12.9 (s, 1H);8.75-8.65 (m, 1.1H); 8.55 (m, 0.9H); 8.45-8.15 (m, 3H); 6.7 (m, 0.9H);6.1 (m, 0.1H); 4.15 (m, 0.1H); 3.95 (m, 0.9H); 3.8 (m, 3H); 2.2-2.05 (m,4H); 1.75-1.6 (m, 3H). 193 455.1 1.8 (500 MHz, DMSO) 12.95 (s, 1H), 8.71(s, 1H), 8.59 (bd, 2H), 8.36 (d, J = 2.2 Hz, 1H), 8.23 (d, J = 6.9 Hz,1H), 6.82 (s, 1H), 3.82-3.77 (m, 4H), 3.66 (t, J = 10.5 Hz, 4H),2.27-2.20 (m, 2H), 2.20-2.08 (m, 2H), 0.00 (TMS) 194 439.1 1.7 (500 MHz,DMSO) 12.89 (s, 1H), 8.61 (m, 2H), 8.46 (d, J = 9.6 Hz, 1H), 8.36 (s,1H), 8.22 (d, J = 6.9 Hz, 1H), 6.82 (bd, 1H), 3.81-3.79 (m, 4H),3.67-3.63 (m, 2H), 2.23 (t, J = 10.2 Hz, 2H), 2.12 (m, 2H), 0.00 (TMS)195 409.1 1.8 196 427.08 1.7 197 528.9 2 (DMSO-d6) 12.5 (br s, 1H); 8.9(m, 1H); 8.65 (m, 1H); 8.4-8.3 (m, 3H); 6.75 (m, 0.5H); 6.5 (m, 0.5H);4.9 (m, 1H); 4.1-3.7 (m, 4H); 3.1-2.9 (m, 5H); 2.2 (m, 1H); 1.95 (m,2H). 198 409.1 1.9 (500 MHz, MeOD) 8.91 (d, J = 2.2 Hz, 1H), 8.72 (s,1H), 8.55 (d, J = 8.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.03 (t, J =7.6 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H),3.21-3.15 (m, 2H), 1.87 (s, 6H), 0.89 (t, J = 7.2 Hz, 3H). 199 447.11.79 (500 MHz, MeOD) 8.73 (s, 1H), 8.63 (d, J = 9.5 Hz, 1H), 8.57 (m,2H), 8.33 (s, 1H), 8.03 (m, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.74 (t, J =7.7 Hz, 1H), 3.82 (m, 2 H), 2.66 (s, 1.3H), 1.88 (s, 6H). (Peak at 2.66is unidentified.) 200 397.1 1.65 (500 MHz, DMSO-d6) 12.90 (s, 1H), 9.05(s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.16 (d, J = 6.4 Hz,1H), 6.73 (s, 1H), 4.75 (s, 1H), 4.08-4.01 (m, 2H), 3.87 (d, J = 6.5 Hz,1H), 1.93-1.83 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.00 (TMS) 201 445 1.7(DMSO-d6) 12.75 (br s, 1H); 9.0 (dd, 1H); 8.55 (s, 1H); 8.45-8.25 (m,3H); 6.7 (m, 1H); 5.2 (m, 1H); 4.2 (m, 2H); 4.05-3.7 (m, 2H); 3.1 (m,1H); 2.6 (m, 1H). 202 441 2.7 (DMSO-d6) 12.25 (br s, 1H); 8.4 (d, 1H);8.35 (dd, 1H); 8.3 (d, 1H); 8.25 (s, 1H); 8.1 (s, 1H); 4.1 (m, 1H); 3.95(m, 1H); 3.8 (m, 1H); 3.7 (m, 1H); 2.1-2.0 (m, 4H); 1.65 (s, 3H). 203423 1.7 (DMSO-d6) 12.8 (br s, 1H); 8.5-8.2 (m, 5H); 6.7 (m, 1H); 4.0-3.7(m, 4H); 2.2-2.0 (m, 4H); 1.7 (s, 3H). 204 427 1.5 (DMSO-d6) 12.85 (brs, 1H); 9.2-9.0 (m, 1H); 8.7-8.6 (m, 1H); 8.4 (m, 3H); 6.85 (m, 0.8H);6.25 (m, 0.2H); 5.55 (d, 1H); 5.05 (dd, 0.8H); 4.8 (m, 0.2H); 4.2-3.6(m, 4H); 2.8 (m, 1H); 2.3-2.15 (m, 1H). 205 423.1 2 206 441.1 2 207459.1 2.1 (500 MHz, DMSO) 13.17 (s, 1H), 8.87 (s, 1H), 8.80-8.60 (m,2H), 8.40-8.30 (m, 2H), 8.05- 7.94 (m, 1H), 7.89 (d, J = 8.3 Hz, 1H),7.70 (m, 1H), 5.70 (tt, J = 15.1, 3.9 Hz, 1H), 3.40- 3.30 (m, 2H),2.38-2.31 (m, 1H), 2.07 (m, 1H), 1.70 (s, 3H), 0.89 (t, J = 7.5 Hz, 3H).208 477.1 2.2 (500 MHz, DMSO) 8.85 (s, 1H), 8.67-8.55 (m, 3H), 8.39 (s,1H), 7.99 (m, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.69 (m, 1H), 3.86-3.71 (m,2H), 2.40-2.34 (m, 1H), 2.10-2.06 (m, 1H), 1.70 (s, 3H), 0.89 (t, J =7.5 Hz, 3H). 209 359.1 1.6 (500 MHz, MeOD) 8.48 (dd, J = 2.8, 9.3 Hz,1H), 8.43 (s, 1H), 8.35-8.33 (m, 1H), 8.28- 8.27 (m, 1H), 3.21 (q, J =7.2 Hz, 2H), 1.77- 1.75 (m, 2H), 1.29 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).210 395.1 1.7 (500 MHz, DMSO) 12.35 (s, 1H), 8.57 (s, 1H), 8.39 (d, J =6.1 Hz, 2H), 8.31 (d, J = 3.9 Hz, 1H), 8.27-8.25 (m, 2H), 5.95-5.71 (m,1H), 3.45-3.37 (m, 2H), 1.53 (br, 2H), 1.16 (br, 2H). 211 413 1.8 (500MHz, MeOD) 8.46-8.43 (m, 2H), 8.37 (t, J = 4.8 Hz, 1H), 8.27-8.26 (m,1H), 3.90- 3.83 (m, 2H), 1.82 (m, 2H), 1.38 (m, 2H). Multiplet (0.47H)at 8.71, identified as an exchangeable proton that did not fullyexchange, which decreased to 0.38H after 1 h. 212 373.1 1.72 (500 MHz,DMSO-d6) 13.04 (s, 1H), 9.16 (d, J = 3.2 Hz, 1H), 8.82 (s, 1H), 8.66 (d,J = 3.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H),7.64 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.1 Hz, 1H), 3.88-3.84 (m, 1H),1.60 (s, 6H), 0.84 (d, J = 6.2 Hz, 6H), 0.00 (TMS) 213 405.1 1.6 (500MHz, MeOD) 8.83 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H), 8.35 (d, J = 2.3 Hz,1H), 8.18 (m, 1H), 4.21 (t, J = 4.8 Hz, 1H), 4.11 (t, J = 4.8 Hz, 1H),3.37-3.32 (m, 2H), 2.58 (s, 3H), 2.27 (s, 3H), 1.79 (s, 6H). 214 4231.71 (500 MHz, MeOD) 8.79 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H), 8.36 (d, J= 2.3 Hz, 1H), 8.29 (m, 1H), 5.67-5.43 (m, 1H), 3.48-3.38 (m, 2H), 2.58(s, 3H), 2.27 (s, 3H), 1.79 (s, 6H). 215 441 1.8 (500 MHz, MeOD) 8.77(d, J = 2.3 Hz, 1H), 8.56 (s, 1H), 8.44-8.34 (m, 1H), 8.34 (d, J = 2.2Hz, 1H), 3.86-3.79 (m, 2H), 2.58 (s, 3H), 2.28 (s, 3H), 1.79 (s, 6H).216 471 2.9 (500 MHz, DMSO) 12.32 (s, 1H), 8.69 (m, 2H), 8.28-8.13 (m,3H), 4.9-4.75 (m, 1H), 4.7-4.5 (m, 1H), 3.95-3.75 (m, 3H), 2.15-1.95 (m,1H), 1.87 (m, 2H), 1.6 (s, 1H), 1.44-1.41 (m, 1H), 1.1-0.85 (m, 3H) 217439 1.8 (500 MHz, MeOD) 8.77 (s, 1H), 8.22-8.19 (m, 3H), 6.40 (s, 1H),4.69 (s, 1H), 4.32 (bs, 1H), 4.01-3.91 (m, 2H), 2.43-2.38 (m, 1H),2.27-2.16 (m, 2H), 1.86-1.82 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H) 218 4572.7 (500 MHz, MeOD) 8.78-8.77 (m, 1H), 8.20 (d, J = 2.1 Hz, 1H),8.15-8.10 (m, 2H), 4.90 (d, J = 9.4 Hz, 1H), 3.94-3.82 (m, 2H), 2.58-2.40 (m, 1H), 2.24-2.21 (m, 1H), 2.0-2.1 (m, 1H), 1.82 (m, 1H), 1.50 (d,1H), 1.4-1.23 (m, 3H) 219 452.9 2 (500 MHz, MeOD) 8.76 (s, 1H),8.21-8.17 (m, 3H), 6.40 (d, J = 5.9 Hz, 1H), 4.90 (d, J = 9.1 Hz, 1H),4.04-3.88 (m, 2H), 3.63 (s, 1H), 2.53-2.39 (m, 1H), 2.22-2.11 (m, 3H),2.01- 1.92 (m, 1H), 1.60-1.45 (m, 1H), 1.08 (t, J = 7.2 Hz, 2H), 1.01(t, J = 7.1 Hz, 1H), 220 469.1 1.84 (500 MHz, DMSO) 13.52-13.35 (br,1H), 13.12-12.96 (br, 1H), 9.07-8.61 (br, 1H), 8.93 (s, 1H), 8.37 (s,1H), 8.07-7.54 (m, 2H), 7.40-7.27 (br, 1H), 3.02-2.97 (m, 2H), 1.71 (s,6H), 0.72 (t, J = 7.1 Hz, 3H). 221 487.1 1.85 (500 MHz, MeOD) 8.93 (d, J= 2.3 Hz, 1H), 8.61 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.21 (m, 1H),7.98 (s, 1H), 7.31 (s, 1H), 4.20 (t, J = 4.8 Hz, 1H), 4.11 (t, J = 4.9Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.36-3.35 (m, 2H), 1.87 (s, 6H).222 505.1 1.9 (500 MHz, MeOD) 8.89 (d, J = 2.3 Hz, 1H), 8.61 (s, 1H),8.37 (d, J = 2.3 Hz, 1H), 8.33 (m, 1H), 7.99 (s, 1H), 7.32 (s, 1H),5.67-5.43 (m, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.35-3.33 (m, 2H), 1.87(s, 6H). 223 483 1.9 (500 MHz, MeOD) 8.91 (d, J = 2.3 Hz, 1H), 8.62 (s,1H), 8.37 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.31 (s, 1H), 4.07 (s, 3H),4.07 (s, 3H), 3.12-3.08 (m, 2H), 1.86 (s, 6H), 1.33-1.25 (m, 2H), 0.62(t, J = 7.5 Hz, 3H). 224 329.05 1.4 (500 MHz, MeOD) 8.49 (d, J = 3.2 Hz,1H), 8.45-8.40 (m, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.03 (d, J = 7.1 Hz,1H), 6.69 (d, J = 6.9 Hz, 1H), 4.77-4.75 (m, 1H), 3.3 (m overlap withmeoh signal, 2H), 1.61 (d, 7.1 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H), 0.00(TMS) 225 346.93 1.4 226 365 1.4 (500 MHz, MeOD) 8.49 (s, 1H), 8.41 (d,J = 7.9 Hz, 1H), 8.33-8.32 (m, 1H), 8.04 (d, J = 6.9 Hz, 1H), 6.70 (d, J= 6.6 Hz, 1H), 5.84 (t, J = 55.8 Hz, 1H), 3.74-3.44 (2m, 2H), 1.63 (d, J= 7.2 Hz, 3H), 0.00 (TMS) 227 383 1.6 228 391.1 2.3 (500 MHz, DMSO)12.96 (s, 1H), 8.65 (s, 1H), 8.42-8.38 (m, 2H), 8.25 (s, 1H), 8.20 (d, J= 7.0 Hz, 1H), 6.68 (d, J = 6.8 Hz, 1H), 5.76 (t, J = 56.1 Hz, 1H),3.43-3.37 (m, 2H), 2.81- 2.78 (m, 2H), 2.30 (dd, J = 8.6, 18.9 Hz, 2H),2.01 (qn, J = 8.1 Hz, 2H), 0.00 (TMS) 229 409.1 2.4 (500 MHz, DMSO)12.91 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H),8.36 (s, 1H), 8.20 (d, J = 6.7 Hz, 1H), 6.66 (d, J = 6.6 Hz, 1H),3.82-3.79 (m, 2H), 2.84 (m, 2H), 2.32-2.28 (m, 2H), 2.02-1.95 (m, 2H),0.00 (TMS) 230 369.2 1.6 (500 MHz, DMSO) 12.92 (s, 1H), 8.63 (s, 1H),8.47 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.84(s, 1H), 6.65 (d, J = 6.5 Hz, 1H), 2.97 (m, 2H), 2.79 (m, 2H), 2.26 (m,2H), 2.00 (m, 2H), 1.23 (dd, J = 6.9, 14.1 Hz, 2H), 0.54 (t, J = 7.1 Hz,3H), 0.00 (TMS) 231 373.1 1.76 (500 MHz, DMSO-d6) 13.02 (s, 1H), 8.99(s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.16 (d,J = 6.7 Hz, 1H), 7.92 (s, 1H), 6.75 (d, J = 4.9 Hz, 1H), 3.07-3.05 (m,2H), 2.10-1.93 (m, 2H), 1.58 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H), 0.81 (s,3H), 0.00 (TMS) 232 391.1 1.77 (500 MHz, DMSO-d6) 13.66-13.49 (m, 1H),12.96-12.93 (m, 1H), 8.76 (s, 1H), 8.57 (d, J = 10.2 Hz, 1H), 8.37 (s,1H), 8.16-8.13 (m, 2H), 6.68 (d, J = 9.6 Hz, 1H), 4.21 (d, J = 51.9 Hz,2H), 3.28 (q, J = 5.4 Hz, 2H), 2.10- 1.94 (m, 2H), 1.57 (s, 3H), 0.87(t, J = 7.5 Hz, 3H), 0.00 (TMS) 233 409.1 1.87 (500 MHz, DMSO-d6) 13.02(s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 2.2 Hz,1H), 8.35 (s, 1H), 8.18 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 5.6 Hz, 1H),5.86-5.64 (m, 1H), 3.43-3.37 (m, 2H), 2.12-1.93 (m, 2H), 1.59 (s, 3H),0.88 (t, J = 7.5 Hz, 3H), 0.00 (TMS) 234 387.1 1.87 (500 MHz, DMSO-d6)13.56 (s, 1H), 12.89 (s, 1H), 8.89 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H),8.16 (d, J = 6.8 Hz, 1H), 6.63 (s, 1H), 3.24 (s, 3H), 2.94 (s, 2H),2.20-1.87 (m, 2H), 1.57 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.75 (s, 3H),0.00 (TMS) 235 523.1 1.9 236 355.2 1.8 237 373.1 1.8 238 398 2.6(DMSO-d6) 12.56 (m, 1H); 8.80 (m, 0.5H); 8.55 (s, 0.5H); 8.50 (s, 0.5H);8.45 (m, 1.0H); 8.40-8.30 (m, 1.5H); 8.28 (m, 1.5H); 8.10 (m, 0.5H);3.80 (m, 2H); 1.42 (m, 6H) 239 410.9 1.7 (500 MHz, DMSO) (warmed at 100C.) 12.26 (s, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.43 (bs, 1H), 8.38 (s,1H), 8.29 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 6.3 Hz, 1H), 8.13 (bt, 1H),6.46 (d, J = 6.3 Hz, 1H), 3.93-3.83 (m, 2H), 1.62-1.60 (m, 2H),1.23-1.17 (m, 2H), 0.0 (TMS) 240 395 1.6 (500 MHz, CD3OD, RT) 8.8 (m,0.6 H), 8.65 (bt, 1H), 8.5 (s, 1H), 8.45 (bd, 1H), 8.25 (m, 1.3H), 8.1(d, 0.8 H), 6.7 (d, 1H), 3.9 (m, 2H), 1.8 (bm, 2H), 1.35 (bm, 2H), 0(TMS) 241 371.1 1.76 242 393.1 1.77 243 411.1 1.86 244 341.1 1.5 (500MHz, MeOD, rt, contains conformers) 8.77 (dd, J = 2.8, 9.2 Hz, 0.29H),8.54-8.49 (m, 1.66H), 8.31 (d, J = 1.5 Hz, 1H), 8.26-8.24 (m, 0.3H),8.10 (dd, J = 4.3, 7.2 Hz, 0.82H), 6.70 (d, J = 7.3 Hz, 0.29H), 6.66(dd, J = 4.3, 7.2 Hz, 0.71H), 3.27-3.18 (m, 2H), 1.77-1.72 (m, 2H),1.28-1.24 (m, 2H), 1.09 (t, J = 7.1 Hz, 0.98H), 0.96 (t, J = 7.1 Hz,2.2H). 245 359.1 1.6 (500 MHz, MeOD, rt, contains conformers) 8.82-8.72(m, 0.26H), 8.50 (m, 1.67H), 8.43- 8.31 (m, 1.84H), 8.25 (br, 0.26H),8.10 (d, J = 6.4 Hz, 0.72H), 6.70-6.65 (m, 1H), 4.48-4.25 (m, 2H),3.49-3.37 (m, 2H), 1.80 (m, 2H), 1.27 (br, 2H). 246 377.1 1.65 (500 MHz,MeOD, rt, contains conformers) 8.77 (dd, J = 2.8, 9.1 Hz, 0.28H),8.57-8.45 (m, 2.29H), 8.32 (d, J = 1.5 Hz, 1H), 8.27-8.26 (m, 0.29H),8.11 (dd, J = 4.0, 7.1 Hz, 0.74H), 6.72 (d, J = 7.3 Hz, 0.29H), 6.68 (d,J = 7.1 Hz, 0.73H), 5.89-5.60 (m, 1H), 3.59-3.47 (m, 2H), 1.80-1.76 (m,2H), 1.34-1.30 (m, 2H). 247 355.1 1.6 (500 MHz, MeOD, rt, containsconformers) 8.77 (dd, J = 2.8, 9.3 Hz, 0.28H), 8.56-8.50 (m, 1.68H),8.31 (d, J = 1.5 Hz, 1H), 8.26 (dd, J = 4.4, 7.2 Hz, 0.28H), 8.10 (dd, J= 4.4, 7.2 Hz, 0.75H), 6.72-6.70 (m, 0.29H), 6.67 (m, 0.72H), 3.18-3.12(m, 2H), 1.77-1.72 (m, 2H), 1.50 (m, 0.6H), 1.38 (m, 1.57H), 1.29-1.24(m, 2H), 0.87 (t, J = 7.4 Hz, 0.92H), 0.67 (t, J = 7.3 Hz, 2.2H). 248460.9 2.7 (DMSO-d6) 12.4 (s, 1H); 8.9 (m, 1H); 8.65 (s, 1H); 8.35 (d,1H); 8.3 (s, 1H); 8.2 (m, 1H); 5.5 (d, 1H); 4.9 (dd, 1H); 4.3-3.8 (m,4H); 2.7 (m, 1H); 2.2-2.0 (m, 1H). 249 478.9 2.9 (DMSO-d6) 12.4 (s, 1H);8.9 (m, 1H); 8.65 (s, 1H); 8.4 (d, 1H); 8.3 (m, 1H); 8.2 (m, 1H); 5.05(m, 1H); 4.3 (m, 2H); 3.9 (m, 2H); 3.0 (m, 1H); 2.5 (m, 1H). 250 3731.59 (500 MHz, MeOD) 8.81 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.36 (d, J= 2.1 Hz, 1H), 7.99 (s, 1H), 3.98 (s, 1H), 3.19 (q, J = 7.2 Hz, 2H),2.31 (s, 3H), 1.79 (s, 6H), 0.90 (t, J = 7.2 Hz, 3H). 251 391 1.61 (500MHz, DMSO) 13.07-12.73 (br, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H),8.36 (d, J = 1.8 Hz, 1H), 8.12 (s, 1H), 8.09 (br, 1H), 4.18 (t, J = 5.1Hz, 1H), 4.08 (t, J = 5.1 Hz, 1H), 3.27 (q, J = 5.3 Hz, 1H), 3.22 (q, J= 5.3 Hz, 1H), 2.24 (s, 3H), 1.65 (s, 6H). 252 409.1 1.69 (500 MHz,MeOD) 8.79 (d, J = 2.1 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H),8.32 (br, 1H), 8.01 (s, 1H), 5.58 (m, 1H), 3.48-3.42 (m, 2H), 2.31 (s,3H), 1.79 (s, 6H). 253 427.1 1.77 (500 MHz, MeOD) 8.78 (s, 1H), 8.46(br, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.01 (s, 1H), 3.85- 3.82 (m, 2H),2.32 (s, 3H), 1.79 (s, 6H). Unidentified peak at d 1.94. 254 387 1.66(500 MHz, MeOD) 8.81 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.36 (d, J = 2.0Hz, 1H), 8.00 (s, 1H), 3.98 (s, 1H), 3.12-3.09 (m, 2H), 2.31 (s, 3H),1.79 (s, 6H), 1.33 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H). 255 344 2 (500MHz, MeOD) 8.79 (br, 0.27H), 8.59 (d, J = 8.9 Hz, 0.69H), 8.53 (s, 1H),8.47 (s, 1H), 8.24 (s, 1H), 3.17 (m, 2H), 1.66 (s, 6H), 1.08 (br,0.93H), 0.91 (m, 2.14H). 256 385 1.9 257 403 1.8 258 421 2 259 399.1 2260 428 2.7 (500 MHz, MeOD) 9.07 (s, 0.33H), 8.78 (s, 0.56H), 8.57-8.31(m, 3.58H), 3.88 (m, 2H), 2.18 (m, 1H), 2.05-2.03 (m, 1H), 1.66 (m, 3H),0.96 (t, J = 7.4 Hz, 3H). 261 412 2.5 (500 MHz, MeOD) 8.80 (m, 0.35H),8.56-8.47 (m, 3.2H), 8.40 (m, 0.36H), 8.26 (m, 1H), 3.85 (m, 2H), 2.18(m, 1H), 2.04 (m, 1H), 1.66 (m, 3H), 0.96 (t, J = 7.5 Hz, 3H). 262 3602.1 263 445 2.4 (DMSO-d6) 12.3 (br s, 1H); 8.9 (m, 1H); 8.4 (d, 1H);8.35 (d, 1H); 8.25 (s, 1H); 8.2 (s, 1H); 5.5 (d, 1H); 4.9 (dd, 1H);4.3-3.75 (m, 4H); 2.7 (m, 1H); 2.2-2.0 (m, 1H). 264 463 2.8 (DMSO-d6)12.3 (br s, 1H); 8.9 (dd, 1H); 8.4-8.3 (m, 2H); 8.25-8.2 (m, 2H); 5.05(d, 1H); 4.35 (m, 2H); 3.9 (m, 2H); 3.0 (m, 1H); 2.5 (m, 1H). 265 432.22.6 (CD3CN) 10.40 (s, 1H), 8.80 (s, 1H), 8.29 (m, 3H), 6.97 (m, 1H),5.22 (m, 1H), 4.79 (m, 1H), 4.43 (dt, 2H), 3.49 (dt, 2H), 2.54 (m, 1H),2.43 (m, 1H), 2.39 (m, 1H), 2.22 (m, 1H) 266 450.2 2.7 (CD3CN) 10.48 (s,1H), 8.79 (s, 1H), 8.30 (m, 3H), 7.01 (t, 1H), 5.90 (tt, 1H), 5.24 (m,1H), 5.83 (m, 1H), 3.60 (m, 2H), 2.53 (m, 1H), 2.42 (m, 1H), 2.36 (m,1H), 2.21 (m, 1H) 267 468.2 2.86 (CD3CN) 10.38 (s, 1H), 8.79 (s, 1H),8.29 (m, 3H), 7.21 (t, 1H), 5.21 (m, 1H), 4.83 (m, 1H), 3.99 (m, 1H),3.86 (m, 1H), 2.51 (m, 1H), 2.45 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H) 268450.1 1.88 269 450.1 1.93 270 374.1 2.3 (500 MHz, MeOD) 9.05 (s, 0.32H),8.84 (s, 0.65H), 8.53 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 3.27-3.17 (m,2H), 2.18-2.10 (m, 1H), 2.07-2.00 (m, 1H), 1.64 (m, 3H), 1.08 (m, 1H),0.95 (t, J = 7.4 Hz, 5H). 271 358 2.1 (500 MHz, MeOD) 8.78 (br, 0.33H),8.58 (d, J = 8.6 Hz, 0.81H), 8.53 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H),3.26-3.16 (m, 2H), 2.17-2.13 (m, 1H), 2.01 (m, 1H), 1.71-1.57 (m, 3H),0.95 (t, J = 7.5 Hz, 6H). 272 450 2.4 (500 MHz, MeOD) 8.87 (s, 1H), 8.56(bt, 1H), 8.53 (s, 1H), 8.43 (d, J = 6.9 Hz, 1H), 8.35 (d, J = 2.2 Hz,1H), 6.91 (d, J = 6.7 Hz, 1H), 5.09 (apparent d, 1H), 4.86 (apparent d,1H), 4.02-3.96 (m, 1H), 3.87- 3.81 (m, 1H), 2.03 (m, 1H), 1.88-1.80 (m,2H), 1.48-1.43 (m, 1H), 0.00 (TMS) 273 464.1 2.5 (500 MHz, MeOD) 8.86(d, J = 2.1 Hz, 1H), 8.44 (t, 1H), 8.40 (s, 1H), 8.37 (d, J = 6.6 Hz,1H), 8.31 (d, J = 2.2 Hz, 1H), 6.52 (bs, 1H), 4.85 (s, 2H), 3.93 (m,2H), 2.86 (m, 2H), 2.72 (m, 2H), 2.25 (m, 1H), 2.06 (m, 1H), 0.00 (TMS)274 428 2.4 (DMSO-d6) (rotational mixture about 1.3:1): 12.6 (m, 1H);9.0 (dd, 0.6H); 8.8 (dd, 0.4H); 8.65-8.3 (m, 4H); 5.6-5.35 (m, 1H); 4.8(t, 0.6H); 4.7 (t, 0.4H); 4.35 (m, 0.4H); 4.2 (m, 0.6H) 4.1-3.7 (m, 3H);2.75-2.6 (m, 1H); 2.25-2.05 (m, 1H). 275 428 2.3 (DMSO-d6) (rotationalmixture about 1.3:1): 12.6 (m, 1H); 8.7-8.25 m, 5H); 5.5-5.3 (m, 1H);4.9 (d, 0.6H); 4.75 (d, 0.4H); 4.1-3.7 (m, 4H); 2.75-2.6 (m, 1H);2.4-2.3 (m, 1H). 276 444 2.5 (DMSO-d6) (rotational mixture about 1.3:1):12.7 (m, 1H); 9.0-8.3 (m, 5H); 5.6-5.4 (m, 1H); 4.8 (t, 0.6H); 4.7 (t,0.4H); 4.4-3.75 (m, 4H); 2.8-2.6 (m, 1H); 2.25-2.05 (m, 1H). 277 473 2.3(DMSO-d6) 12.35 (m, 1H); 8.75-8.6 (m, 2H); 8.35-8.15 (m, 3H); 4.75 (m,1H); 4.0-3.7 (m, 4H); 2.3 (m, 1H); 2.0 (m, 1H); 1.35 (s, 3H). 278 4872.5 (DMSO-d6) 12.35 (m, 1H); 8.75-8.6 (m, 2H); 8.35-8.15 (m, 3H); 4.75(m, 1H); 4.0-3.7 (m, 4H); 2.3 (m, 1H); 2.0 (m, 1H); 1.6 (m, 2H); 1.0 (m,3H). 279 468.1 1.59 280 455 1.5 (DMSO-d6) 13.05-12.9 (m, 1H); 8.8-8.25(m, 5H); 6.75 (m, 0.7H); 6.35 (m, 0.3H); 4.95 (m, 0.7H); 4.75 (m, 0.3H);4.05-3.6 (m, 4H); 2.4-2.1 (m, 2H); 1.4 (m, 3H). 281 469 1.6 (DMSO-d6)13.0-12.9 (m, 1H); 8.8-8.25 (m, 5H); 6.7 (m, 0.7H); 6.3 (m, 0.3H); 5.05-4.8 (m, 1H); 4.1-3.6 (m, 4H); 2.4-2.05 (m, 2H); 1.75-1.6 (m, 2H);1.05-0.9 (m, 3H). 282 392.9 2.7 (500 MHz, MeOD) 8.80 (d, J = 2.3 Hz,1H), 8.35 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 2.3 Hz, 1H), 3.19 (q, J =7.2 Hz, 2H), 1.74 (s, 6H), 0.93 (t, J = 7.2 Hz, 3H). 283 410.9 2.7 (500MHz, MeOD) 8.81 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.33 (s, 1H), 8.28(d, J = 2.2 Hz, 1H), 8.19-8.17 (m, 0.33H), 4.23 (dt, J = 47.4, 5.1 Hz,2H), 3.42 (dt, J = 25.5, 5.1 Hz, 2H), 1.75 (s, 6H). 284 439.9 1.9 (500MHz, MeOD) 8.72 (s, 1H), 8.57-8.53 (m, 2H), 8.45 (s, 1H), 8.26 (s, 1H),3.85-3.78 (m, 2H), 1.75 (s, 6H). 285 428 2.8 (500 MHz, MeOD) 9.07 (d, J= 1.9 Hz, 0.53H), 8.81-8.78 (m, 0.84H), 8.55 (d, J = 10.5 Hz, 1H), 8.45(d, J = 15.6 Hz, 1H), 8.30 (s, 1H), 4.56- 4.52 (m, 1H), 4.06-4.00 (m,1H), 3.89-3.84 (m, 1H), 2.34-2.24 (m, 1H), 1.12-1.06 (m, 6H). 286 428.92.9 (500 MHz, MeOD) 8.79 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.33-8.28(m, 2.8H), 5.64 (tt, J = 56.5, 4.2 Hz, 1H), 3.51-3.43 (m, 2H), 1.74 (s,6H). 287 446.9 3 (500 MHz, MeOD) 8.78 (d, J = 2.3 Hz, 1H), 8.45 (t, J =6.1 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J = 3.3 Hz, 2H), 3.86-3.44 (m, 2H),1.73 (s, 6H). 288 437.96 2.9 (500 MHz, MeOD) 9.24 (m, 0.5H), 8.87-8.73(m, 0.27H), 8.62-8.29 (m, 2.7H), 7.76-7.37 (m, 0.46H), 3.86-3.76 (m,2H), 1.80-1.50 (m, 6H). 289 403.5 2.9 (DMSO-d6) 12.3 (br s, 1H); 8.7 (s,1H); 8.3-8.2 (m, 2H); 8.1 (s, 1H); 7.65 (m, 1H); 4.1-3.85 (m, 2H);3.15-2.9 (m, 2H); 2.1-1.9 (m, 4H); 1.6 (s, 3H); 0.8 (m, 3H). 290 421.52.9 (DMSO-d6) 12.3 (br s, 1H); 8.7 (s, 1H); 8.25 (m, 2H); 8.1 (s, 1H);7.95 (m, 1H); 4.35-4.05 (m, 3H); 3.95 (m, 1H); 3.35-3.2 (m, 2H); 2.1-1.9(m, 4H); 1.6 (s, 3H). 291 439.5 3 (DMSO-d6) 12.3 (br s, 1H); 8.7 (s,1H); 8.3 (m, 2H); 8.15-8.05 (m, 2H); 5.8 (dd, 1H); 4.1 (m, 1H); 3.9 (m,1H); 3.4 (m, 2H); 2.1-1.9 (m, 4H); 1.6 (s, 3H). 292 417.1 2.7 (DMSO-d6)12.3 (s, 1H); 8.7 (s, 1H); 8.25 (m, 2H); 8.1 (s, 1H); 7.7 (dd, 1H); 4.1(m, 1H); 3.9 (m, 1H); 3.1-2.8 (m, 2H); 2.1-1.9 (m, 4H); 1.6 (s, 3H);1.35-1.15 (m, 2H); 0.6 (m, 3H). 293 455.1 2.09 294 483.1 2.42 295 4532.02 296 410.3 1.75 297 407.1 2.3 (DMSO-d6): 12.45 (br s, 1H); 8.7 (s,1H); 8.4-8.2 (m, 4H); 5.5 (d, 1H); 4.75 (t, 1H); 4.25-3.9 (m, 2H);3.2-3.0 (m, 2H); 2.6-2.0 (m, 2H); 1.0 (m, 3H). 298 421.2 2.5 (DMSO-d6)12.4 (br s, 1H); 8.7 (s, 1H); 8.4-8.2 (m, 4H); 5.5 (d, 1H); 4.75 (t,1H); 4.25-3.9 (m, 2H); 3.8 (m, 1H); 3.0 (m, 1H); 2.3-2.0 (m, 2H);1.45-1.2 (m, 2H); 0.75 (m, 3H). 299 425.1 2.3 (DMSO-d6) 12.4 (br s, 1H);8.7 (s, 1H); 8.6 (m, 1H) 8.35-8.2 (m, 3H); 5.5 (d, 1H); 4.8 (t, 1H);4.45 (m, 1H); 4.3-3.9 (m, 3H); 3.3 (m, 1H); 2.7 (m, 1H); 2.3-2.0 (m,2H). 300 443.1 2.5 (DMSO-d6) 12.4 (br s, 1H); 8.8-8.6 (m, 2H); 8.4-8.2(m, 3H); 5.9 (dd, 1H); 5.5 (d, 1H); 4.85 (t, 1H); 4.3-3.9 (m, 2H);2.75-2.0 (m, 4H). 301 441.1 2.6 302 465.2 1.9 303 411.2 1.8 304 447.21.8 305 425.2 1.9 306 437.2 1.8 307 455.2 2 308 437.2 1.9 309 457.1 1.8(DMSO-d6) 12.3 (br s, 1H); 8.75 (s, 1H); 8.35-8.2 (m, 3H); 8.1 (s, 1H);6.45 (m, 1H); 5.55 (m, 1H); 4.2-3.7 (m, 4H); 2.4-2.2 (m, 2H); 1.7 (s,3H).

TABLE 6 Cmpd # M + H RT NMR 310 409.00 1.80 DMSO-d6: 12.25 (br s, 1H);8.8 (m, 1H); 8.7 (m, 1H); 8.35-8.3 (m, 2H); 8.2 (m, 1H); 7.2 (m, 1H);4.85 (d, 1H); 4.0 (m, 1H); 3.95-3.8 (m, 3H); 2.35 (m, 1H); 2.1-1.85 (m,3H). 311 409.00 1.80 DMSO-d6: 12.25 (br s, 1H); 8.8 (m, 1H); 8.7 (m,1H); 8.35-8.3 (m, 2H); 8.2 (m, 1H); 7.2 (m, 1H); 4.85 (d, 1H); 4.0 (m,1H); 3.95-3.8 (m, 3H); 2.35 (m, 1H); 2.1-1.85 (m, 3H). 312 444.90 2.20500 MHz DMSO-d6 @60 C.: 12.8 (br m, 1H), 8.85 (m, 1H), 8.8 (m, 1H), 8.65(s, 1H), 8.3 (d, 1H), 8.25 (1H), 7.75 (br m, 1H), 7.3 (d, 1H), 4.85 (m,1H), 3.9 (m, 2H), 3.0 (d m, 2H), 2.2 (s, 3H) 313 495.00 2.30 314 438.002.00 500 MHz MeOD-d4: 8.68 (m, 1H), 8.5 (s, 1H), 8.35 (s, 1H), 8.1(d.1H), 6.71 (d, 1H), 4.04 (m, 1H), 3.99m, 1H), 2.7 (t, 2H), 2.4 (m,1H), 2.24 (m, 1H) 315 456.00 2.80 500 MHz MeOD-d4: 8.66 (s, 1H), 8.4 (s,1H), 8.35 (d, 1H), 8.3 (d.1H), 5.45 (m, 1H, parially ex), 5.04 (m, 1H),4.01m, 1H), 3.93 (m, 1H), 2.73 (t, 2H), 2.5 (m, 1H), 2.32 (m, 1H) 316488.00 2.10 500 MHz MeOD-d4: 8.77 (s, 1H), 8.71 (s, 1H), 8.5 (d, 1H),8.35 (s. 1H), 8.02 (t, 1H), 7.88 (d, 1H), 7.71 (t, 1H), 5.25 (m, 1H),4.02 (m, 1H), 3.90 (m, 1H) 2.73 (t, 2H), 2.6 (m, 1H), 2.5 (m, 1H) 317482.00 2.70 DMSO d5 12.8 (bs, 1H); 8.7 (bs, 1H); 8.5 (m, 2H); 8.4 (s,1H); 7.7 (s, 1H); 6.9 (s, 1H); 4.8 (m, 1H); 3.8 (m, 2H); 3.6 (m, 3H); 29(m, 2H); 2.0 (m, 2H); 1.2 (m, 2H) 318 496.10 2.90 DMSO d5 12.6 (bs, 1H);8.8 (bs, 1H); 8.7 (m, 2H); 8.4 (s, 1H); 7.7 (s, 1H); 6.9 (s, 1H); 4.8(m, 1H); 3.8 (m, 2H); 3.6 (m, 2H); 3.5 (m, 5H); 2.0 (m, 2H); 1.2 (t, 3H)319 510.10 3.10 DMSO d5 12.6 (bs, 1H); 8.9 (bs, 1H); 8.6 (m, 2H); 8.4(s, 1H); 7.8 (s, 1H); 4.7 (m, 1H); 3.9 (m, 2H); 3.7 (m, 2H); 3.3 (m,2H); 2.0 (m, 2H); 1.5 (m, 2H); 0.9 (t, 3H) 320 508.10 3.00 DMSO d5 12.6(bs, 1H); 8.8 (bs, 1H); 8.6 (m, 2H); 8.4 (s, 1H); 7.7 (s, 1H); 4.7 (m,1H); 4.0 (m, 2H); 3.8 (m, 2H); 2.9 (s, 1H); 2.0 (m, 2H); 1.9 (m, 3H);0.8 (t, 2H); 0.6 (m, 1H) 321 424.20 1.50 (d4-methanol) 8.86 (d, 1H),8.40 (d, 1H), 8.29 (d, 1H), 8.25 (s, 1H), 7.30 (dd, 1H), 5.65 (br s,1H), 4.62 (d, 1H), 4.03-3.35 (m, 7H) 322 403.10 2.10 DMSO-d6: 12.5 (s,1H); 8.7 (s, 1H); 8.3 (m, 3H); 7.9 (d, 1H); 4.65 (d, 1H); 3.95 (m, 1H);3.85 (m, 2H); 2.25 (m, 1H); 2.0 (m, 3H); 1.05 (m, 3H). 323 395.10 1.70(500 MHz, DMSO-d6) d 12.31 (s, 1H), 8.79 (s, 1H), 8.65 (d, J = 7.8 Hz,1H), 8.61 (t, J = 6.3 Hz, 1H), 8.38 (d, J = 4.1 Hz, 1H), 8.29 (dd, J =4.7, 1.5 Hz, 1H), 8.24 (s, 1H), 7.15 (dd, J = 7.9, 4.7 Hz, 1H), , 3.81(m, 2H), 1.57 (t, 2H), 1.19 (t, 2H) 324 385.20 1.70 DMSO-d6: 13.0 (br s,1H); 8.7-8.6 (m, 2H); 8.4 (m, 1H); 8.3 (m, 1H); 8.15 (d, 0.3H); 8.0 (d,0.7H); 6.75 (d, 0.7H); 6.3 (d, 0.3H); 4.85 (d, 0.7H); 4.5 (0.3H);4.0-3.85 (m, 1H); 3.8- 3.6 (m, 2H); 2.35 (m, 1H); 2.05 (m, 3H); 1.1 (dd,2H); 0.95 (dd, 4H). 325 399.10 2.10 DMSO-d6: 12.4 (br s, 1H); 8.65 (s,1H); 8.55 (m, 1H); 8.3 (m, 2H); 8.25 (s, 1H); 4.7 (d, 1H); 3.95 (m, 1H);3.85 (m, 2H); 3.8 (m, 1H); 3.0 (s, 1H); 2.25 (m, 1H); 2.0 (m, 3H). 326452.39 3.60 CD3OD/CDCl3: 1.68 (6H, s), 2.14 (2H, m), 3.38 (2H, m), 7.98(1H, t), 8.22 (1H, s), 8.28 (1H, s), 8.54 (1H, s), 8.83 (1H, s) 327438.41 3.56 CD3OD/CDCl3: 1.70 (6H, s), 3.81 (2H, m), 7.59 (1H, m), 8.22(1H, s), 8.26 (1H, s), 8.45 (1H, t), 8.58 (1H, s), 8.81 (1H, s) 328404.34 3.23 DMSO-d6/CD3OD/CDCl3: 1.58 (6H, s), 3.12 (1H, s), 3.75 (2H,m), 7.21 (1H, m), 8.19 (1H, s), 8.28 (1H, m), 8.45 (1H, t), 8.69 (1H,s), 8.71 (1H, d) 329 470.35 3.24 MeOD: 1.75 (6H, s), 2.16 (2H, m), 3.35(2H, m), 8.34 (2H, s), 8.48 (1H, s), 8.75 (1H, s), 8.85 (1H, s) 330381.20 1.50 DMSO-d6: 12.8 (s, 1H); 8.7-8.5 (m, 3H); 8.4-8.25 (m, 2H);6.7 (m, 0.7H) 6.3 (m, 0.3H); 4.8 (m, 0.7H); 4.6 (m, 0.3H); 4.0-3.6 (m,4H); 2.95 (m, 1H); 2.35 (m, 1H); 2.05 (m, 3H). 331 383.20 1.70 DMSO-d6:12.9 (br s, 1H); 8.8 (s, 1H); 8.7 (s, 1H); 8.6 (s, 1H); 8.4 (s, 1H);8.15 (m, 1H); 6.8 (s, 1H); 4.7 (s, 1H); 4.05-3.85 (m, 2H); 3.1 (s, 1H);2.25 (m, 1H); 1.1-0.95 (m, 6H). 332 387.40 2.00 DMSO-d6: 12.95 (br s,1H); 8.7 (s, 1H); 8.6 (s, 1H); 8.4 (s, 1H); 8.15 (m, 2H); 6.8 (s, 1H);4.6 (s, 1H); 3.9 (m, 1H); 2.25 (m, 1H); 1.1-0.95 (m, 12H). 333 400.202.00 DMSO-d6: 12.35 (br s, 1H); 8.77 (dd, 1H); 8.65 (s, 1H); 8.3 (m,2H); 8.2 (s, 1H); 4.7 (d, 1H); 4.1 (m, 2H); 3.95 (m, 1H); 3.8 (m, 1H);2.25 (m, 1H); 2.0 (m, 3H). 334 382.20 1.50 DMSO-d6: 12.9 (br s, 1H);8.95 (dd, 1H); 8.75 (m, 0.4H); 8.6 (m, 1.6H); 8.4-8.3 (m, 2H); 6.75 (d,0.8H); 6.35 (d, 0.2H); 4.9 (d, 0.8H); 4.65 (d, 0.2H); 4.2-4.0 (m, 2H);3.8 (m, 1H); 3.6 (m, 1H); 2.35 (m, 1H); 2.1-2.0 (m, 3H). 335 387.40 2.00336 403.40 1.90 337 385.40 1.80 338 511.20 2.50 DMSO-d6: 8.60 (m, 2H);8.30 (s, 1H); 8.23 (bs, 1H); 5.50 (m, 2H); 4.38 (m, 2H); 4.10 (m, 2H);3.38 (m, 4H); 2.50 (m, 1H); 1.90-2.00 (m, 3H); 1.32 (t, 3H) 339 421.302.00 340 455.20 2.10 341 439.20 1.90 DMSO-d6: 13.0 (bs, 1H); 8.55 (m,1H); 8.45 (m, 1H); 8.35 (m, 1H); 6.72 (m, 1H); 5.60 (m, 1H); 4.20-3.70(m, 5H); 3.30 (s, 3H); 2.00 (m, 3H) 342 457.10 2.40 DMSO-d6: 8.30 (m,1H); 8.30 (m, 3H); 7.70 (m, 1H); 5.40 (m, 1H); 4.20-3.70 (m, 5H); 3.30(s, 3H); 2.00 (m, 3H) 343 379.20 2.04 (500 MHz, DMSO) 12.83 (s, 1H),9.30 (s, 1H), 8.61 (t, J = 7.6 Hz, 2H), 8.37 (d, J = 4.5 Hz, 1H), 8.17(d, J = 7.1 Hz, 1H), 7.27 (dd, J = 4.7, 7.7 Hz, 1H), 6.69 (d, J = 6.9Hz, 1H), 3.79-3.76 (m, 2H), 1.63 (s, 6H) 344 366.10 1.87 DMSO-d6: 12.5(m, 1H); 8.95 (m, 0.5 H); 8.78 (m, 0.5H); 8.65 (m, 0.5H); 8.52 (m,0.5H); 8.48 (s, 1H); 8.32-8.25 (m, 2H); 8.30 (m, 1.5H); 8.12 (m, 1H);7.20 (m, 1H); 4.54 (m, 1H); 3.80 (m, 2H); 1.32 (m, 3H) 345 411.20 1.90(500 MHz, DMSO-d6) 12.20 (s, 1H), 8.67 (dd, J = 1.4, 7.9 Hz, 1H), 8.43(t, J = 6.2 Hz, 1H), 8.32-8.28 (m, 2H), 8.10 (s, 1H), 7.5 (bs, 1H), 7.20(dd, J = 4.7, 7.9 Hz, 2H), 3.81-3.73 (m, 2H), 2.20-2.16 (m, 1H),1.99-1.95 (m, 1H), 1.56 (s, 3H), 0.82 (t, J = 7.5 Hz, 3H) 346 393.201.60 (DMSO-d6, 300 MHz) 11.95 (bs, 1H), 8.7 (d, 1H), 8.25 (m, 2H), 8.12(d, 1H), 8.02 (d, 1H), 7.28 (s, 1H), 7.13 (dd, 1H), 6.38 (bd, 1H), 3.75(m, 2H), 2.06 (m, 1H), 1.83 (m, 1H), 1.46 (s, 3H), 0.8 (t, 3H); 347425.27 2.25 (500 MHz, MeOD) 8.87 (d, J = 8.1 Hz, 1H), 8.60 (t, 1H), 8.36(d, 1H), 8.27-8.26 (m, 2H), 7.39 (dd, J = 5.0, 8.0 Hz, 1H), 3.86 (m,2H), 2.29 (t, J = 7.5 Hz, 4H), 0.87 (t, J = 7.5 Hz, 6H) 348 407.20 1.67(500 MHz, DMSO-d6) d 12.81 (s, 1H), 8.92 (s, 1H), 8.68-8.57 (m, 3H),8.38 (d, J = 3.3 Hz, 1H), 8.17 (d, 1H), 7.30-7.27 (m, 1H), 6.82 (d, 1H),3.82-3.74 (m, 2H), 2.26-2.12 (m, 2H), 2.12-2.05 (m, 2H), 0.82-0.78 (m,6H) 349 373.40 1.74 350 407.40 1.72 CD3CN: 9.89 (s, 1H), 8.79 (d, 1H),8.27 (m, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.18 (m, 2H), 6.49 (d, 1H),5.80 (s, 1H), 3.97 (m, 1H), 3.59 (m, 1H), 1.53 (s, 3H), 1.02 (dd, 6H)351 425.40 1.40 DMSO-d6: 12.2 (br s, 1H); 8.85 (m, 1H); 8.7 (d, 1H); 8.3(m, 2H); 8.15 (m, 1H); 7.2 (m, 1H); 4.9 (dd, 1H); 4.45 (m, 1H); 4.05-3.7(m, 4H); 2.3 (m, 1H); 1.95 (m, 1H). 352 407.40 1.40 DMSO-d6: 12.8 (br s,1H); 9.1 (m, 1H); 8.7- 8.6 (m, 2H); 8.45-8.3 (m, 2H); 7.4 (m, 0.3H); 7.3(m, 0.7H); 6.85 (d, 0.7H); 6.35 (d, 0.3H); 5.1 (dd, 0.7H); 4.8 (dd,0.3H); 4.5 (m, 1H); 4.2-3.6 (m, 4H); 2.4 (m, 1H); 2.1 (m, 1H). 353401.40 1.95 354 387.40 1.87 355 369.30 1.69 356 409.40 2.25 357 423.301.90 358 405.40 1.80 359 399.10 1.80 DMSO-d6: 12.7 (br s, 1H); 8.8 (s,1H); 8.7- 8.2 (s, 3H); 6.5 (m, 0.8H); 6.2 (m, 0.2H); 4.2 (m, 0.3H); 4.0(m, 0.7H); 3.8-3.6 (m, 2H); 3.4 (m, 1H); 3.2-3.05 (m, 1H); 2.7 (m, 2H);2.2 (m, 3H); 2.05 (m, 1H); 1.7 (s, 2.7H); 1.6 (s, 0.3H); 1.0 (m, 0.3H);0.7 (m, 2.7H). 360 379.20 1.60 DMSO-d6: 11.92 (m, 1H); 8.72 (bs, 1H);8.22 (m, 1H); 8.05 (m, 2H); 7.42 (m, 1H); 7.18 (m, 1H); 6.32 (bs, 1H);5.22 (m, 1H); 4.20 (m, 2H); 3.32 (s, 3H); 1.35 (m, 3H) 361 397.10 1.90DMSO-d6: 11.9 (m, 1H); 8.55 (m, 1H); 8.25 (m, 1H); 8.18 (m, 1H); 7.98(m, 1H); 7.65 (m, 1H); 7.15 (m, 1H); 5.15 (m, 1H); 4.18 (m, 2H); 3.30(s, 2.5H); 2.90 (s, 0.5H); 1.35 (m, 3H) 362 357.10 1.51 363 343.10 1.40364 361.10 1.41 365 391.10 1.85 366 393.10 1.60 (500 MHz, DMSO) 12.83(s, 1H), 9.2 (bs, 1H), 9.07 (s, 1H), 8.68 (d, J = 7.8 Hz, 1H), 8.61 (s,1H), 8.42 (d, J = 4.6 Hz, 1H), 8.15 (d, J = 7.1 Hz, 1H), 7.35 (dd, J =4.8, 7.8 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.86 (t, J = 6.3 Hz, 1H),4.12-4.04 (m, 1H), 3.90-3.85 (m, 1H), 2.31 (t, J = 6.6 Hz, 1H), 1.02 (d,6H) 367 410.91 2.10 (500 MHz, DMSO) 12.36 (s, 1H), 8.86 (t, J = 6.3 Hz,1H), 8.72 (dd, J = 1.4, 7.9 Hz, 1H), 8.35-8.31 (m, 3H), 7.86 (s, 1H),7.26 (dd, J = 4.7, 7.9 Hz, 1H), 4.60 (t, J = 7.6 Hz, 1H), 4.04- 3.96 (m,1H), 3.90-3.83 (m, 1H), 2.28 (td, J = 13.8, 6.9 Hz, 1H), 1.02 (t, 6H),368 474.00 1.60 369 490.00 1.80 370 504.10 1.90 371 477.00 1.50 372491.00 1.60 373 409.00 1.40 DMSO-d6: 12.9 (m, 1H); 8.95-8.85 (m, 1H);8.8-8.65 (m, 2H); 8.55-8.3 (m, 2H); 7.4 (m, 0.3H); 7.3 (m, 0.7H); 6.85(d, 0.7H); 6.5 (d, 0.3H); 5.55 (d, 1H); 5.2 (d, 0.7H); 5.0 (d, 0.3H);4.3-3.8 (m, 4H); 2.8-2.6 (m, 1H); 2.5- 2.4 (m, 1H). 374 427.00 1.60DMSO-d6: 12.8 (br s, 1H); 9.1 (m, 1H); 8.7- 8.35 (m, 4H); 7.3 (m, 1H);6.8 (m, 0.7H); 6.5 (m, 0.3H); 5.3 (m, 0.7H); 5.1 (m, 0.3H); 4.3 (m, 2H);3.9 (m, 2H); 3.15 (m, 1H); 2.65 (m, 1H). 375 409.00 1.40 DMSO-d6: 12.9(m, 1H); 9.25-9.1 (m, 1H); 8.75-8.6 (m, 2H); 8.45-8.35 (m, 2H); 7.4 (m,0.3H); 7.3 (m, 0.7H); 6.9 (d, 0.7H); 6.3 (d, 0.3H); 5.6 (d, 1H); 5.1(dd, 0.7H); 4.9 (dd, 0.3H); 4.5 (m, 0.3H); 4.2 (m, 0.7H); 4.3-3.6 (m,3H); 2.8 (m, 1H); 2.3-2.1 (m, 1H). 376 343.10 1.37 377 361.10 1.48 378325.10 1.37 379 339.10 1.49 380 397.10 1.60 381 379.10 1.99 382 429.351.70 (500 MHz, MeOD) 8.83 (d, J = 8 Hz, 2H), 8.68 (s, 1H), 8.59-8.57 (m,2H), 8.42-8.41 (m, 1H), 8.07-8.03 (m, 1H), 7.90 (dd, J = 4.4, 8.2 Hz,1H), 7.77-7.73 (m, 1H), 7.41 (m, 1H), 3.83-3.76 (m, 2H), 1.88 (s, 6H).383 423.00 2.10 DMSO-d6: 12.3 (s, 1H); 8.7 (d, 1H); 8.45-8.25 (m, H);8.15 (s, 1H); 7.25 (m, 1H); 4.15 (m, 1H); 4.0 (m, 1H); 3.85 (m, 1H); 3.7(m, 1H); 2.05 (m, 4H); 1.75 (s, 3H). 384 405.10 1.50 DMSO-d6: 12.8 (s,1H); 8.8-8.2 (m, 5H); 7.4 (m, 0.2H); 7.25 (m, 0.8H); 6.8 (d, 0.8H); 6.15(d, 0.2H); 4.2 (m, 0.2H); 3.95 (m, 0.8H); 3.8 (m, 3H); 2.2-2.0 (m, 4H);1.8-1.6 (m, 3H). 385 488.00 1.70 386 380.00 1.90 DMSO-d6: 12.4 (bs, 1H);8.92 (m, 0.5H); 8.62 (m, 0.5H); 8.50 (s, 0.5H); 8.42 (s, 0.5H);8.40-8.20 (m, 4H); 7.20 (m, 0.5H); 7.15 (m, 0.5H); 3.72 (m, 2H); 1.45(m, 6H) 387 421.10 1.50 (500 MHz, DMSO) 12.81 (s, 1H), 8.65-8.56 (m,3H), 8.36 (d, J = 4.4 Hz, 1H), 8.22 (d, J = 6.9 Hz, 1H), 7.26 (dd, J =4.7, 7.9 Hz, 1H), 6.85 (d, J = 6.4 Hz, 1H), 3.80 (bm, 4H), 3.66- 3.62(m, 2H), 2.26-2.22 (m, 2H), 2.15 (m, 2H), 0.00 (TMS) 388 453.30 1.68(500 MHz, MeOD) 8.88 (dd, J = 1.5, 8.1 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J= 3.1 Hz, 1H), 8.32-8.26 (m, 1H), 7.99 (s, 1H), 7.40 (dd, J = 4.7, 8.0Hz, 1H), 7.31 (s, 1H), 4.19 (t, J = 4.8 Hz, 1H), 4.11-4.09 (m, 1H), 4.07(s, 3H), 4.07 (s, 3H), 3.35-3.32 (m, 2H), 1.87 (s, 6H), 1.38- 1.29 (m,2H, impurity). 389 489.00 1.78 (500 MHz, MeOD) 8.82 (dd, J = 1.4, 8.1Hz, 1H), 8.58 (s, 1H), 8.52 (m, 1H), 8.40 (d, J = 3.2 Hz, 1H), 8.00 (s,1H), 7.39 (dd, J = 4.7, 8.0 Hz, 1H), 7.32 (s, 1H), 4.08 (s, 3H), 4.07(s, 3H), 3.80-3.77 (m, 2H), 1.87 (s, 6H). 390 471.10 1.70 (500 MHz,MeOD) 8.85 (dd, J = 1.4, 8.1 Hz, 1H), 8.60 (s, 1H), 8.42-8.40 (m, 1H),8.37- 8.30 (m, 1H), 8.00 (s, 1H), 7.40 (dd, J = 4.7, 8.0 Hz, 1H), 7.32(s, 1H), 5.64-5.41 (m, 1H), 4.08 (s, 3H), 4.07 (s, 3H), 3.44 (m, 2H),1.87 (s, 6H). 391 449.20 1.70 (500 MHz, MeOD) 8.88-8.87 (m, 1H), 8.59(s, 1H), 8.40 (d, J = 3.3 Hz, 1H), 8.03-8.02 (m, 1H), 7.99 (s, 1H), 7.40(dd, J = 4.7, 8.1 Hz, 1H), 7.31 (s, 1H), 4.07 (s, 3H), 4.07 (s, 3H),3.07 (m, 2H), 1.86 (s, 6H), 1.29 (m, 2H), 0.61 (t, J = 7.5 Hz, 3H). 392339.10 1.45 393 353.10 1.56 394 357.10 1.47 395 375.10 1.56 396 427.001.90 DMSO-d6: 12.25 (s, 1H); 8.95 (m, 1H); 8.7 (d, 1H); 8.35 (d, 1H);8.3 (m, 1H); 8.2 (m, 1H); 7.25 (dd, 1H); 5.5 (d, 1H); 4.95 (dd, 1H);4.3- 3.75 (m, 4H); 2.7 (m, 1H); 2.2-2.0 (m, 1H). 397 445.00 2.30DMSO-d6: 12.15 (s, 1H); 8.9 (m, 1H); 8.65 (d, 1H); 8.35 (d, 1H); 8.3 (m,1H); 8.15 (m, 1H); 7.2 (m, 1H); 5.1 (m, 1H); 4.3 (m, 2H); 3.9 (m, 2H);3.0 (m, 1H); 2.5 (m, 1H). 398 394.00 2.10 (500 MHz, MeOD) 9.14 (m,0.25H), 8.95 (d, J = 6.7 Hz, 0.66H), 8.59-8.41 (m, 3.64H), 7.45 (m, 1H),3.84 (m, 2H), 2.21-2.18 (m, 1H), 2.05-2.02 (m, 1H), 1.67 (m, 3H), 0.97(t, J = 7.3 Hz, 3H). 399 325.90 1.60 400 340.00 1.80 (500 MHz, MeOD)9.07 (br, 0.24H), 8.54 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 4.3 Hz, 1H),7.39-7.36 (m, 1H), 3.25-3.15 (m, 2H), 2.19- 2.00 (m, 2H), 1.65 (m, 3H),0.97-0.90 (m, 6H). 401 410.10 2.10 DMSO-d6 (rotational mixture about1.3:1): 12.45 (m, 1H); 9.05-8.3 (m, 5H); 7.3-7.2 (m, 1H); 5.6-5.4 (m,1H); 4.8 (t, 0.6H); 4.7 (t, 0.4H); 4.45 3.75 (m, 4H); 2.8-2.6 (m, 1H);2.25-2.1 (m, 1H). 402 410.10 2.00 DMSO-d6 (rotational mixture about1.3:1): 12.45 (m, 1H); 8.8-8.3 m, 5H); 7.3-7.15 (m, 1H); 5.5-5.35 (m,1H); 4.9 (d, 0.6H); 4.75 (d, 0.4H); 4.15-3.8 (m, 4H); 2.75-2.6 (m, 1H);2.4-2.3 (m, 1H). 403 392.10 2.00 404 409.10 1.50 405 409.00 1.50

Example 3 JAK3 Inhibition Assay

Compounds were screened for their ability to inhibit JAK3 using theassay shown below. Reactions were carried out in a kinase buffercontaining 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl₂, 25 mM NaCl, and0.01% BSA. Substrate concentrations in the assay were 5 μM ATP (200uCi/μmole ATP) and 1 μM poly(Glu)₄Tyr. Reactions were carried out at 25°C. and 1 nM JAK3.

To each well of a 96 well polycarbonate plate was added 1.5 μl of acandidate JAK3 inhibitor along with 50 μl of kinase buffer containing 2μM poly(Glu)₄Tyr and 10 μM ATP. This was then mixed and 50 μl of kinasebuffer containing 2 nM JAK3 enzyme was added to start the reaction.After 20 minutes at room temperature (25° C.), the reaction was stoppedwith 50 μl of 20% trichloroacetic acid (TCA) that also contained 0.4 mMATP. The entire contents of each well were then transferred to a 96 wellglass fiber filter plate using a TomTek Cell Harvester. After washing,60 μl of scintillation fluid was added and ³³P incorporation detected ona Perkin Elmer TopCount.

Example 4 JAK2 Inhibition Assay

The assays were as described above in Example 3 except that JAK-2 enzymewas used, the final poly(Glu)₄Tyr concentration was 15 μM, and final ATPconcentration was 12 μM.

All compounds depicted in Tables 1, 2 and 3 were found to inhibit JAK3with a Ki of less than 0.1 μM except for compounds 22, 35, 56, 68, 177,223, 310, 317, 318, 319, 320, 321, 322, 326, 336, 337, 338, 339, 340,351, 356, 367, 369, 370, 388, and 390. All Table 1, 2 and 3 compoundsinhibited JAK3 with a Ki of less than 2.0 μM except for compounds 68 and319. All Table 1, 2 and 3 compounds were found to inhibit JAK2 with a Kiof less than 0.5 μM except for compounds 9, 22, 35, 56, 57, 68, 310,317, 38, 319, 320, 321, 336, 338, 339, 340, 348, 351, 356, 367 and 372.All Table 1, 2 and 3 compounds inhibited JAK2 with a Ki of less than 5.0μM except for compounds 68, 318 and 319.

Example 5 JAK3 Cellular Inhibition Assay

HT-2 clone A5E cells (ATCC Cat. # CRL-1841) were grown and maintained at37° C. in a humidified incubator in cell culture medium (RPMI 1640supplemented with 2 mM L-glutamine adjusted to contain 1.5 g/L sodiumbicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 0.05mM 2-mercaptoethanol, 10% fetal bovine serum, and 10% by volume ratT-STIM factor [Fisher Scientific Cat # CB40115] with Con A). On the dayof the experiment, HT-2 cells were washed, resuspended at a density of5×10⁶ cells per ml in fresh cell culture medium without T-STIM andincubated for 4 hours without T-STIM. After four hours, 50 μl (0.25×10⁶cells) of the resuspended cells were added to each well of a 96 wellplate. Serial dilutions of compounds were made in DMSO and then added toRPMI. 100 μl of the diluted compounds were added to each well and theplates were incubated for 1 hour at 37° C. 50 μl of recombinant murineinterleukin-2 (rmIL-2) at 40 ng/ml (R & D systems Inc. Cat #402-ML) wasadded and the plates were incubated for 15 minutes at 37° C.

The plates were then centrifuged for 5 minutes at 1000 rpm, thesupernatant was aspirated and 50 μl of 3.7% formaldehyde in phosphatebuffered saline (PBS) was added per well. The plates were incubated for5 minutes at room temperature on a plate shaker. The plates were againcentrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated, 50μl of 90% methanol was added to each well, and the plate was incubatedon ice for 30 minutes. The supernatant was aspirated and the platewashed with PBS. 25 μl per well of 1:10 diluted Phospho STAT-5 (Y694) PEconjugated antibody (PS-5 PE antibody; Becton-Dickinson Cat. #61256) wasadded to the plates and the plates were incubated for 45 minutes at roomtemperature on a plate shaker. 100 μl PBS was added and the plates werecentrifuged. The supernatant was aspirated and the cells resuspended in100 μl PBS. The plate was then read on a 96 well FACS reader (GuavaPCA-96).

Compounds of the invention were found to inhibit JAK3 in this assay.

Example 6 JAK2 Cellular Inhibition Assay

TF-1 cells (ATCC Cat. # CRL-2003) were grown and maintained at 37° C. ina humidified incubator in cell culture medium (RPMI 1640 supplementedwith 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate,4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 10% fetal bovineserum and recombinant human granulocyte-macrophage colony stimulatingfactor [rhGMCSF, R&D Systems Inc. Cat. #215-GM]). On the day of theexperiment, TF-1 cells were washed, resuspended at a density of 5×10⁶cells per ml in fresh cell culture medium without rhGMCSF and incubatedfor 4 hours without rhGMCSF. After four hours, 50 μl (0.25×10⁶ cells) ofthe resuspended cells were added to each well of a 96 well plate. Serialdilutions of compounds were made in DMSO and then added to RPMI. 100 μlof the diluted compounds were added to each well and the plates wereincubated for 1 hour at 37° C. 50 μl of rhGMCSF at 10 ng/ml was addedand the plates were incubated for 15 minutes at 37° C. The plates werethen processed for FACS analysis as detailed above in Example 5.Compounds of the invention were found to inhibit JAK2 in this cellularassay.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example above.

1-44. (canceled)
 45. A method of treating or lessening the severity of adisease of condition selected from a proliferative disorder, a cardiacdisorder, a neurodegenerative disorder, an autoimmune disorder, acondition associated with organ transplantation, an inflammatorydisorder, or an immunologically mediated disorder in a patient,comprising the step of administering to said patient a compound offormula (I):

or a pharmaceutically acceptable salt thereof, wherein: R³ is H, Cl orF; X¹ is N or CR⁴; R² is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH₂,CONHR′, CON(R′)₂, or CN; R⁴ is H, F, R′, OH, OR′, COR′, COOH, COOR′,CONH₂, CONHR′, CON(R′)₂, or CN; or R² and R⁴, taken together, form a 5-7membered aryl or heteroaryl ring optionally substituted with 1-4occurrences of R¹⁰; R′ is a C₁₋₃ aliphatic optionally substituted with1-4 occurrences of R⁵; each R⁵ is independently selected from halogen,CF₃, OCH₃, OH, SH, NO₂, NH₂, SCH₃, NCH₃, CN or unsubstituted C₁₋₂aliphatic, or two R⁵ groups, together with the carbon to which they areattached, form a cyclopropyl ring or C═O; each R¹⁰ is independentlyselected from halogen, OCH₃, OH, NO₂, NH₂, SH, SCH₃, NCH₃, CN orunsubstituted C₁₋₂aliphatic; R¹ is

R″ is H or is a —C₁₋₂ aliphatic optionally substituted with 1-3occurrences of R¹¹; each R¹¹ is independently selected from halogen,OCH₃, OH, SH, NO₂, NH₂, SCH₃, NCH₃, CN, CON(R¹⁵)₂ or unsubstituted C₁₋₂aliphatic, or two R¹¹ groups, together with the carbon to which they areattached, form a cyclopropyl ring or C═O; R⁶ is a C₁₋₄ aliphaticoptionally substituted with 1-5 occurrences of R¹²; each R¹² isindependently selected from halogen, OCH₃, OH, NO₂, NH₂, SH, SCH₃, NCH₃,CN or unsubstituted C₁₋₂aliphatic, or two R¹² groups, together with thecarbon to which they are attached, form a cyclopropyl ring; Ring A is a4-8 membered saturated nitrogen-containing ring comprising up to twoadditional heteroatoms selected from N, O or S and optionallysubstituted with 1-4 occurrences of R¹³; each R¹³ is independentlyselected from halogen, R′, NH₂, NHR′, N(R′)₂, SH, SR′, OH, OR′, NO₂, CN,CF₃, COOR′, COOH, COR′, OC(O)R′ or NHC(O)R′; or any two R¹³ groups, onthe same substituent or different substituents, together with theatom(s) to which each R¹³ group is bound, form a 3-7 membered saturated,unsaturated, or partially saturated carbocyclic or heterocyclic ringoptionally substituted with 1-3 occurrences of R⁵; R⁸ is C₁₋₄ aliphaticsubstituted with 1-5 occurrences of R¹²; R⁹ is C₁₋₂ alkyl; or R⁸ and R⁹are taken together to form a 3-7 membered carbocyclic or heterocyclicsaturated ring optionally substituted with 1-5 occurrences of R¹²; R¹⁴is H or unsubstituted C₁₋₂ alkyl; R¹⁵ is H or unsubstituted C₁₋₂ alkyl;and R⁷ is a C₂₋₃ aliphatic or cycloaliphatic optionally substituted withup to 6 occurrences of F.
 46. The method of claim 45, comprising theadditional step of administering to said patient an additionaltherapeutic agent selected from a chemotherapeutic or anti-proliferativeagent, an anti-inflammatory agent, an immunomodulatory orimmunosuppressive agent, a neurotrophic factor, an agent for treatingcardiovascular disease, an agent for treating diabetes, or an agent fortreating immunodeficiency disorders, wherein said additional therapeuticagent is appropriate for the disease being treated.
 47. The methodaccording to claim 45, wherein the disease or disorder is allergic ortype I hypersensitivity reactions, asthma, diabetes, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, AIDS-associateddementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease),multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia, stroke, baldness, transplant rejection, graftversus host disease, rheumatoid arthritis, a solid malignancy, ahematologic malignancy, a leukemia, a lymphoma and a myeloproliferativedisorder.
 48. The method according to claim 47, wherein said disease ordisorder is asthma.
 49. The method according claim 47, wherein saiddisease or disorder is transplant rejection.
 50. The method accordingclaim 47, wherein said disease or disorder is rheumatoid arthritis. 51.The method according to claim 47, wherein said disease is amyeloproliferative disorder selected from polycythemia vera, essentialthrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasiawith myelofibrosis, chronic myeloid leukemia, chronic myelomonocyticleukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome orsystematic mast cell disease.
 52. The method according to claim 45,wherein the compound of Formula (I) has formula I-A:


53. The method according to claim 52, wherein R³ is H or Cl.
 54. Themethod according to claim 52, wherein R² is H, F, R′, OH or OR′.
 55. Themethod according to claim 52, wherein the compound is of formula I-A andR⁴ is H, F, R′, OH or OR′, or R² and R⁴ are taken together to form a6-membered aryl ring.
 56. The method according to claim 52, wherein R⁷is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F orCH₂CH₂CHF₂.
 57. The method according to claim 52, wherein R″ is H orCH₃.
 58. The method according to claim 52, wherein R⁸, R⁹ and the carbonatom to which they are attached form


59. The method according to claim 52, wherein R⁸ and R⁹ are takentogether to form a ring selected from

wherein one or more carbon atoms in of said ring are optionally andindependently replaced by N, O or S.
 60. The method according to claim52, wherein Ring A is

and R^(13,) is H or R¹³.